Immunohistochemical expression of Parathyroid hormone-related protein and Ezrin in Invasive Breast Carcinoma of No Special Type: A retrospective Analysis

Immunohistochemical expression of Parathyroid hormone-related protein and Ezrin in Invasive Breast Carcinoma of No Special Type: A retrospective Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Immunohistochemical expression of Parathyroid hormone-related protein and Ezrin in Invasive Breast Carcinoma of No Special Type: A retrospective Analysis Menna Allah Shalaby, Marwa Dawoud, Marwa Gadallah, Asmaa Abdou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4744381/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Jan, 2025 Read the published version in Diagnostic Pathology → Version 1 posted 7 You are reading this latest preprint version Abstract Background Globally, breast cancer ranks among the most common malignancies and has a high mortality rate. Invasive breast carcinoma of no special type (IBC-NST) presents a heterogeneous group with variable prognosis. Identifying reliable biomarkers is crucial for improving treatment strategies and predicting outcomes. This study investigates the immunohistochemical expression of parathyroid hormone-related protein (PTHrP) and ezrin in IBC-NST and their correlation with clinicopathological features and overall survival. Methods This retrospective study analyzed 160 paraffin-embedded tissue samples, including 123 IBC-NST and 37 normal breast tissues, collected from patients treated at Menoufia University Hospital during the period from January 2018 to January 2022. Immunohistochemical staining for PTHrP and ezrin was performed, and expression levels were quantified using the H score. Results PTHrP expression was significantly higher in IBC-NST than in adjacent DCIS and normal tissues (p < 0.001). High PTHrP percent of expression was associated with metastasis (p = 0.009), bone metastasis (p = 0.012), and lymphovascular invasion (p = 0.037). Ezrin expression was also significantly elevated in IBC-NST, with higher H score values correlating with high tumor grade (p = 0.002), high N stage (p = 0.045), advanced AJCC stage grouping (p = 0.0043) and metastasis (p = 0.001). A significant positive correlation was observed between PTHrP and ezrin expression (rs = 0.341, p < 0.001). Kaplan-Meier analysis showed that high ezrin expression, in terms of intensity (p = 0.007) and H score (p = 0.002), was linked to poorer survival. Conclusion The study highlights the significant roles of PTHrP and ezrin in breast cancer progression. Elevated levels of these proteins are associated with more aggressive disease, suggesting their capability as prognostic indicators and treatment targets in breast cancer. Additional studies are required to investigate their interaction and collective influence on breast cancer metastasis and treatment. Breast carcinoma Ezrin Immunohistochemistry Parathyroid hormone-related protein (PTHrP) Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 1 Introduction Breast cancer remains one of the most common cancers globally, as reported by the GLOBOCAN 2020 data, ranking as the fifth leading cause of cancer-related mortality, with approximately 2.3 million new cases diagnosed annually ( 1 ). In Egypt, the incidence of breast cancer is somewhat lower compared to the USA and Western nations, yet the mortality rate among Egyptian patients is notably higher ( 2 ). Invasive breast carcinoma of no special type (IBC-NST) is the most frequently occurring among the different types of breast cancer, yet it presents a heterogeneous group with variable prognoses driven by diverse molecular characteristics that are not yet fully understood ( 3 ). Identifying reliable biomarkers that predict therapeutic response and clinical outcome is crucial as treatment paradigms evolve. Despite advances in early detection and management, the persistent issues of recurrence, metastasis, and therapeutic resistance underscore the imperative of advancing our understanding of the underlying molecular drivers of breast cancer ( 4 , 5 ). In this context, exploring the role of key molecular markers such as parathyroid hormone-related protein (PTHrP) and ezrin offers promising pathways. PTHrP and ezrin have emerged as potentially significant biomarkers in several cancers, including breast cancer ( 6 – 8 ). Parathyroid hormone-related protein (PTHrP) is synthesized in both normal breast tissue and breast cancer cells, where it induces bone destruction when secreted by cancer cells metastasized to the bone. Upon release, PTHrP interacts with its receptor on adjacent bone cells. However, in the context of breast cancer, PTHrP does not follow this binding mechanism. Instead, it travels within the cells, exerting either tumor-promoting or tumor-suppressing effects ( 9 ). Similarly, ezrin, a protein belonging to the ezrin-radixin-moesin (ERM) family, is pivotal in metastasis. It connects the cytoskeleton to the plasma membrane, thereby affecting cell adhesion, mobility, and the signaling pathways essential for tumor progression and regulation of tumor metastasis in several cancers, including breast cancer ( 7 , 8 ). Some studies suggest that both PTHrP and ezrin are not only overexpressed in various malignancies but also correlate with poor prognostic outcomes ( 6 , 10 ). However, their expression and prognostic value, specifically in IBC-NST, remain underexplored. This gap in knowledge presents a significant limitation for the stratification of patients and the tailoring of therapeutic strategies. Interestingly, the interplay between PTHrP and ezrin in breast cancer has not been previously explored. This study investigates the interaction between PTHrP and ezrin within the specific setting of IBC-NST. By evaluating their immunohistochemical expression and correlation, this research aims to clarify their prognostic value in breast cancer. 2 Patients and Methods This retrospective analysis was conducted on 160 archival paraffin-embedded tissue blocks collected from patients diagnosed with IBC-NST and normal breast tissue at the Menoufia University Hospital, Pathology Department, during the period from January 2018 to January 2022. Ethical clearance for this study was obtained from the Institutional Review Board (IRB) under code no (3/2022PATHO33). The study group was divided into 123 cases of IBC-NST, treated primarily by modified radical mastectomy in 103 cases and conservative breast surgery in 20 cases, and 37 control cases comprising normal breast tissue samples obtained from reduction mammoplasty. Exclusion criteria included prior neoadjuvant therapy, other histological types rather than IBC-NST, and core biopsy specimens. 2.1 Clinicopathological data Clinicopathological data were gathered from medical records. Histopathological evaluations were performed on sections stained with hematoxylin and eosin. Tumor staging adhered to the most recent TNM classification guidelines set by the American Joint Committee on Cancer (AJCC) ( 11 ). Tumors were categorized into early-stage (T1 and T2) and advanced-stage (T3 and T4). Grading was conducted using the Elston and Ellis grading system (1991) ( 12 ) and the Nottingham Prognostic Index was assessed ( 13 ). Tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment ( 14 ), the presence and extent of DCIS and perineural as well as lymphovascular invasion were evaluated​​​​ ( 15 , 16 ). Mitotic figures were quantified as described by Lehr et al. (2012) ( 17 ). The molecular classification was determined based on the immunostaining results for ER, PR, Her2neu, and Ki67 ( 18 ). 2.2 Tissue microarray (TMA) blocks For immunohistochemical analysis, tissue microarrays (TMAs) were created using a manual tissue arrayer (Breecher Instrument Manual Microarray, Wisconsin, USA). Each TMA block contained duplicate cores from each tissue sample, ensuring adequate sampling. 2.3 Immunohistochemical analysis The primary antibodies employed included a mouse monoclonal antibody for PTHrP (concentrated at 100 µl with a 1:100 dilution, Chongqing Biospes, Catalog # YMA1281) and a rabbit polyclonal antibody for ezrin (concentrated at 100 µl with a 1:150 dilution, ABclonal, Catalog # A19048), following an overnight incubation at dilutions recommended by the manufacturers. Standardized protocols using tris-EDTA buffer were employed for antigen retrieval, with specific controls (normal kidney for PTHrP and colon carcinoma for ezrin) in place for each staining batch ​( 19 – 21 ). Quantitative and qualitative assessments of immunohistochemical staining were systematically performed, evaluating both the staining patterns and intensities across samples. The semiquantitative H-score was utilized to integrate the proportion and intensity of staining, providing a composite expression score for each marker ( 22 ). 2.4 Survival Data Analysis Survival analyses utilized data from Menoufia University's Clinical Oncology and Nuclear Medicine Department, spanning a follow-up period from January 2018 to January 2022. Kaplan-Meier and Hazard function curves were constructed to illustrate survival trends and associations ( 23 ). 2.5 Statistical analysis The data were managed and analyzed using IBM SPSS software version 20.0. (Armonk, NY: IBM Corp). Continuous data were reported as means and standard deviations (SD), whereas categorical data were represented as frequencies and percentages. Depending on suitability, categorical variables were compared using the Chi-square or Monto-Carlo tests. The Student's t-test was applied for normally distributed quantitative variables, whereas the Kruskal-Wallis test was used for non-normally distributed quantitative variables. Survival analysis was conducted using the Kaplan-Meier method. The Cox proportional hazards model was used to identify independent prognostic factors. A p-value below 0.05 was deemed statistically significant. 3 Results 3.1 Clinicopathological Data of Breast Cancer Cases The clinicopathological characteristics of the studied cases are detailed in Table 1. 3.2 Immunohistochemical Expression of PTHrP in the Studied Groups PTHrP was expressed in all investigated cases, either benign or malignant, as a cytoplasmic pattern of expression. There was a significant progressive increase in the percent of PTHrP expression from normal breast (mean ± SD of 64.86 ± 11.58, median of 65.0) to adjacent DCIS lesions (mean ± SD of 68.06 ± 7.92, median of 65.0) peaking in IBC-NST cases (mean ± SD of 80.53 ± 8.91, median of 80.0) (p < 0.001). Similarly, there was a progressive increase in PTHrP H score values from normal breast (mean ± SD 97.97 ± 37.18, median of 80.0) to adjacent DCIS lesions (mean ± SD 186.5 ± 36.77, median of 195.0) peaking in IBC-NST cases (mean ± SD 209.51 ± 49.86, median of 210.0) (p < 0.001). (Table 2 and Fig. 1). 3.3 Relationship Between PTHrP Expression and Clinicopathological Data in Breast Cancer Tissues In IBC cases, high PTHrP percent expression was significantly associated with the presence of metastasis (p = 0.009), bone metastasis (p = 0.012), and lymphovascular invasion (p = 0.037) (Fig. 2 ). High PTHrP H score values were significantly associated with postmenopausal status (p = 0.044), presence of metastasis (p = 0.007), luminal subtype (p = 0.038), ER positivity (p = 0.032), and PR positivity (p = 0.005) (Fig. 3 ). 3.4 Immunohistochemical Expression of Ezrin in the Studied Groups Ezrin was expressed in 59.5% of the control group, all adjacent DCIS lesions, and 92.7% of the IBC-NST group as a cytoplasmic pattern of expression. There was a significant progressive increase in the percent of ezrin expression from the normal breast (mean ± SD of 67.05 ± 8.95, median of 70.0) to adjacent DCIS lesions (mean ± SD of 67.74 ± 8.25, median of 70.0) peaking in IBC-NST cases (mean ± SD of 79.25 ± 8.15, median of 80.0) (p < 0.001). Similarly, there was a progressive increase in ezrin H score values from normal breast (mean ± SD 75.23 ± 22.70, median of 70.0) to adjacent DCIS lesions (mean ± SD 157.4 ± 46.0, median of 160.0) peaking in IBC-NST cases (mean ± SD 200.4 ± 53.13, median of 210.0) (p < 0.001). (Table 3 and Fig. 4 ). 3.5 Relationship Between Ezrin Expression and Clinicopathological Data in Breast Cancer Tissues In IBC cases, elevated ezrin H score values were notably linked to high tumor grade (p = 0.002), high N stage (p = 0.045), advanced AJCC stage grouping (p = 0.043), presence of metastasis (p = 0.001), higher grade (p = 0.033), and a greater extent of DCIS and perineural invasion (p = 0.031) (Fig. 5 ). Additionally, there was a significant positive correlation between elevated ezrin H score and both increased mitotic activity (p = 0.002) and higher NPI score (p = 0.003) (Fig. 6 ). 3.6 Relationship Between PTHrP and Ezrin Expression in Breast Cancer Tissues A highly significant direct correlation was observed between PTHrP and ezrin expression regarding percent (rs = 0.238, p = 0.011) and H score values (rs = 0.341, p < 0.001) (Fig. 7 ). 3.7 Overall Survival Analysis Overall survival data were available for 94 cases (76.4%). The follow-up period extended from January 2018 to December 2022, with survival time ranging from 9 to 52 months (mean ± SD: 30.15 ± 11.25 months, median: 30 months). During this period, 29 patients (23.6%) died of their disease. Prolonged overall survival was associated with moderate intensity (p = 0.007) and Low H score values (p = 0.002) of ezrin (Fig. 8 ). However, the Multivariate Cox regression analysis showed no significant ezrin expression independence in breast cancer patients' overall survival. 4 Discussion Parathyroid hormone-related protein (PTHrP) is a recognized factor in breast cancer pathogenesis, particularly concerning bone metastasis ( 24 ). The results of the current study revealed that PTHrP expression was significantly elevated in IBC cases compared to adjacent DCIS lesions and normal breast tissues. This finding aligns with previous studies that have shown elevated PTHrP levels in more aggressive breast cancer subtypes ( 6 )​​​​. Specifically, PTHrP expression in the present study was associated with poor prognostic factors such as lymphovascular invasion, metastasis, and bone metastasis. These findings align with those of Yoshida et al. (2000) ( 25 ), who observed that elevated PTHrP expression is associated with the progression of breast tumors, the development of bone metastases, and reduced overall patient survival. Additionally, Powell et al. (1991) ( 26 ) reported a higher prevalence of PTHrP expression in breast cancer bone metastases compared to other metastatic sites. PTHrP has been shown to promote angiogenesis at skeletal metastasis sites, which may aid in tumor cell spread, colonization, and growth ( 27 – 29 ). Its enhancement of various angiogenic factors, such as IL-6, IL-8, CXCL1, and CCL2/MCP-1, likely contributes to the development and progression of tumors that produce PTHrP. An additional explanation for PTHrP's role in bone metastasis comes from an experimental model using the estrogen receptor-positive human MCF7 breast cancer cell line. These cells stayed dormant in bone after being injected into nude mice but started to aggressively colonize bone and form lytic deposits when PTHrP was overexpressed ( 30 ). Gene expression analysis indicated that overexpression of PTHrP led to the downregulation of several pro-dormancy genes. This included LIFR and its downstream signaling target, SOCS3 ( 31 ). Our study also found a significant association between high PTHrP H score values and positive hormone receptor status (ER and PR), luminal subtype, and postmenopausal status. These findings are in line with the work of Henderson et al. (2001) ( 32 ) who reported that PTHrP expression was correlated with ER and PR positivity and better differentiation in breast cancer tissues. On the other hand, the study's high PTHrP levels in primary tumors were associated with reduced bone metastases and better prognosis​​. This discrepancy might be due to differences in study populations or methodologies, highlighting the complexity of PTHrP's role in breast cancer progression. In literature, some studies ( 33 , 34 ) reported that ER positivity was linked to a higher incidence and increased risk of bone metastasis. Another study connected PTHrP with ER and discovered that the expression of ER, OPNcyt, and PTHrPR1 proteins in primary breast cancers might be linked to a higher risk of bone metastasis ( 35 ). Other studies ( 34 , 36 ) reported that the luminal subtype was identified as the most prevalent phenotype among patients with bone metastasis. The role of PTHrP in breast cancer remains complex, with its expression being influenced by various factors, including its actions on parathyroid hormone receptor (PTHR) and stage of tumorigenesis, which may affect its prognostic significance ( 9 ). Regarding Ezrin expression, the results of this study revealed that it was significantly upregulated in IBC cases compared to adjacent DCIS lesions and normal tissues. High ezrin expression was associated with poor prognostic factors such as advanced AJCC stage, higher tumor grade, advanced N stage, and presence of metastasis and perineural invasion​​. These results align with the work of Ma et al. (2008) ( 37 ), who reported that increased ezrin expression was positively correlated with lymph node involvement, indicating that ezrin may serve as a biomarker for predicting lymphatic metastasis in breast carcinoma. Moreover, Xu et al. (2014) discovered that ezrin expression was linked to lymph node involvement and a high histological grade, corroborating our findings ( 38 ). Our study further showed that ezrin expression was significantly correlated with higher mitotic activity and NPI score, indicating that higher ezrin levels are associated with more aggressive tumor behavior. These findings are consistent with previous reports demonstrating a link between ezrin overexpression and increased metastatic potential in various cancer types ( 39 , 40 ). The relocation of ezrin from the apical membrane in normal breast epithelial cells to the cytoplasm in invasive breast cancer cells suggests a functional role of ezrin in promoting tumor invasion and metastasis ( 20 ). Ezrin is believed to facilitate breast cancer cell migration and invasion through the induction of EMT. Studies have demonstrated that silencing ezrin results in breast cancer cells adopting an epithelial morphology and losing their migratory ability. In contrast, overexpression of ezrin leads to a dispersed, spindle-shaped morphology. Additionally, ezrin-depleted cells exhibited higher levels of epithelial markers (E-cadherin and ZO-1) and lower levels of Vimentin, Snail, Slug, and MMP9, whereas the opposite pattern was observed in cells with ezrin overexpression ( 41 ). Considering the significance of angiogenesis in cancer metastasis and progression ( 42 ), the role ezrin plays in breast cancer angiogenesis was previously investigated, and it was found that vascular mimicry and the microtubule formation ability of HUVECs decreased in cells with ezrin depletion but increased in cells with ezrin overexpression. Further Western blot analysis showed that silencing ezrin reduced the expression levels of VEGF and HIF1α, while overexpression of ezrin increased these levels, indicating that ezrin may possess pro-angiogenic properties in breast cancer ( 41 ). Kaplan-Meier survival analysis in our study indicated that higher ezrin expression, both in terms of intensity and H score, was associated with poorer prognosis and reduced overall survival in breast cancer patients. These findings are supported by previous studies that have demonstrated the prognostic value of ezrin in predicting poor outcomes in breast cancer ​​ ( 39 , 40 ). Our study revealed a significant correlation between PTHrP and ezrin expression in breast cancer tissues. Elevated ezrin levels were found to correlate with increased PTHrP levels, indicating a possible interaction or joint regulation between these proteins. This co-expression could contribute to tumor growth and metastasis, thereby serving as important prognostic biomarkers and potential therapeutic targets in breast cancer therapy. Although the relationship between PTHrP and ezrin has not been extensively studied in breast cancer, similar interactions have been observed in other cancers, such as lung cancer bone metastases, where TGF-β induced both ezrin and PTHrP expression, facilitating tumor growth ( 43 )​​​​. The co-expression of PTHrP and ezrin may indicate a synergistic role in enhancing breast cancer cells' invasive and metastatic potential. Further research is needed to elucidate the underlying mechanisms of their interaction and their combined impact on breast cancer progression. Understanding these pathways could lead to developing novel therapeutic strategies targeting both proteins to inhibit metastasis and improve patient outcomes. Limitations of the study This study has some limitations, including a relatively small sample size and a short follow-up duration, which may affect the generalizability of the results. Additionally, data on patient response to therapy prevents a comprehensive assessment of the therapeutic implications of PTHrP and ezrin expression. Conclusion Our findings highlight the significant roles of PTHrP and ezrin in breast cancer progression and prognosis. Elevated expression levels of these proteins are associated with more aggressive disease. These biomarkers can potentially serve as valuable prognostic tools and therapeutic targets in breast cancer. Further studies are needed to fully understand the mechanisms underlying their co-regulation and their implications in breast cancer metastasis and treatment. Abbreviations AJCC American Joint Committee on Cancer CI Confidence interval DCIS Ductal Carcinoma In situ ERM Ezrin-Radixin-Moesin IBC-NST invasive breast carcinoma of no special type OS Overall survival PTHrP Parathyroid hormone-related protein TILs Tumour-infiltrating lymphocytes TMAs tissue microarrays Declarations Conflict of interests: no conflict of interests Acknowledgments Not applicable. Funding This research received no specific grant from public, commercial, or not-for-profit funding agencies. Contributions All authors contributed equally to this manuscript. Menna Allah G. Shalaby and Asmaa G. Abdou designed and conceptualized the study and managed data preparation. All authors prepared the tissue microarray slides. Marwa M. Dawoud and Marwa S. Gadallah performed the statistical analysis and prepared the figures. All authors drafted the original paper. All authors revised the manuscript for intellectual content and read and approved the final manuscript. Corresponding authors Menna Allah Gamil Ali Shalaby. Ethics declarations This retrospective analysis study received approval from the Institutional Review Board at The Faculty of Medicine and Menoufia University Hospitals, Menoufia University, Egypt (Ethical Code: 3/2022PATHO33). Patient consent was not required. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Data availability The datasets generated and/or analysed during the current study are available from the corresponding author upon request. Researchers interested in accessing the data are encouraged to contact the corresponding author to discuss the conditions under which access may be granted References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al. 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Xu C, Wang F, Hao L, Liu J, Shan B, Lv S et al. Expression Patterns of Ezrin and AJAP1 and Clinical Significance in Breast Cancer. Front Oncol [Internet]. 2022;12(March). https://www.frontiersin.org/articles/ 10.3389/fonc.2022.831507/full . Elliott BE, Meens JA, SenGupta SK, Louvard D, Arpin M. The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells. Breast Cancer Res [Internet]. 2005;7(3):R365. http://breast-cancer-research.biomedcentral.com/articles/ 10.1186/bcr1006 . Li Q, Wu M, Wang H, Xu G, Zhu T, Zhang Y et al. Ezrin silencing by small hairpin RNA reverses metastatic behaviors of human breast cancer cells. Cancer Lett [Internet]. 2008;261(1):55–63. https://linkinghub.elsevier.com/retrieve/pii/S0304383507005459 . Li N, Kong J, Lin Z, Yang Y, Jin T, Xu M et al. Ezrin promotes breast cancer progression by modulating AKT signals. Br J Cancer [Internet]. 2019;120(7):703–13. https://www.nature.com/articles/s41416-019-0383-z . Wang JC, Li XX, Sun X, Li GY, Sun JL, Ye YP et al. Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF-1α-induced pro-angiogenic factor. Cancer Sci [Internet]. 2018;109(5):1627–37. https://onlinelibrary.wiley.com/doi/ 10.1111/cas.13570 . Deng X, Tannehill-Gregg SH, Nadella MVP, He G, Levine A, Cao Y et al. Parathyroid hormone-related protein and ezrin are up-regulated in human lung cancer bone metastases. Clin Exp Metastasis [Internet]. 2007;24(2):107–19. https://link.springer.com/ 10.1007/s10585-007-9059-9 . Tables Table (1): Clinicopathological data of the studied breast cancer cases (n=123). Clinical pathology No. % Age <50 39 31.7 ≥50 84 68.3 Min. – Max. 30.0 – 82.0 Mean ± SD. 55.05 ± 11.86 Median (IQR) 55.0 (47.0–65.0) Menopausal status Premenopausal 55 44.7 Postmenopausal 68 55.3 Multifocality Unifocal 105 85.4 Multifocal 18 14.6 Grade 1 2 1.6 2 103 83.7 3 18 14.6 Size Min. – Max. 0.50 – 15.0 Mean ± SD. 3.73 ± 2.25 Median (IQR) 3.50 (2.0–5.0) T stage T1 37 30.1 T2 56 45.5 T3 24 19.5 T4 6 4.9 T stage grouping Early 93 75.6 Advanced 30 24.4 N stage N0 27 22.0 N1 29 23.6 N2 34 27.6 N3 33 26.8 Nodal metastasis No 27 22.0 Yes 96 78.0 AJCC stage grouping Early 56 45.5 Advanced 67 54.5 Metastasis No 110 89.4 Yes 13 10.6 Bone metastasis No 116 94.3 Yes 7 5.7 Insitu status Absent 92 74.8 Present 31 25.2 Grade of DCIS Low grade 9 7.3 High grade 22 17.9 DCIS Percent Non extensive 15 12.2 Extensive 16 13.0 Mitosis Min. – Max. 1.0 – 23.0 Mean ± SD. 3.87 ± 5.14 Median (IQR) 2.0 (1.0–3.0) NPI group Good 18 14.6 Moderate 49 39.8 Poor 56 45.5 NPI score Min. – Max. 2.40 – 8.0 Mean ± SD. 5.15 ± 1.28 Median (IQR) 5.30 (4.20–6.0) TIL Low 75 61.0 Moderate 26 21.1 Dense 22 17.9 LVI No 115 93.5 Yes 8 6.5 PNI No 114 92.7 Yes 9 7.3 Molecular subtype Luminal 97 78.9 Triple negative 10 8.1 Her2neu enriched 16 13.0 ER Negative 26 21.1 Positive 97 78.9 PR Negative 37 30.1 Positive 86 69.9 Her2neu Negative 75 61.0 Positive 48 39.0 Ki 67 proliferative index Low proliferative index 70 56.9 High proliferative index 53 43.1 Table (2): Comparison of PTHrP expression in different studied groups. PTHrP Control (n = 37) Adjacent DCIS (n= 31) IBC (n = 123) Test of Sig. (p ) No. % No. % No. % Percent Min. – Max. 40.0 – 85.0 60.0 – 90.0 60.0 – 95.0 H(p)= 64.716 * (<0.001 * ) Mean ± SD. 64.86 ± 11.58 68.06 ± 7.92 80.53 ± 8.91 Median (IQR) 65.0 (60.0 – 70.0) 65.0 (60.0 – 70.0) 80.0 (70.0 – 90.0) H score Min. – Max. 50.0 – 170.0 120.0 – 270.0 70.0 – 270.0 H(p)= 77.737 * (<0.001 * ) Mean ± SD. 97.97 ± 37.18 186.5 ± 36.77 209.51 ± 49.86 Median (IQR) 80.0 (70.0 – 120.0) 195.0 (170.0 – 210.0) 210.0 (180.0 – 255.0) IQR: Inter quartile range SD: Standard deviation H: H for Kruskal Wallis test p: p value for comparing different studied groups *: Statistically significant at p ≤ 0.05 Table (3): Comparison of ezrin expression in different studied groups. Ezrin Control (n = 37) Adjacent DCIS (n= 31) IBC (n = 123) Test of Sig. (p) No. % No. % No. % Expression Negative 15 40.5 0 0.0 9 7.3 χ 2 = 27.323 * ( MC p (<0.001 * ) Positive 22 59.5 31 100.0 114 92.7 Percent Min. – Max. 45.0 – 80.0 60.0 – 90.0 60.0 – 90.0 H= 48.930 * (<0.001 * ) Mean ± SD. 67.05 ± 8.95 67.74 ± 8.25 79.25 ± 8.15 Median (IQR) 70.0 (60.0 – 75.0) 70.0 (60.0 – 70.0) 80.0 (70.0 – 90.0) H score Min. – Max. 55.0 – 140.0 60.0 – 240.0 70.0 – 270.0 H= 61.786 * (<0.001 * ) Mean ± SD. 75.23 ± 22.70 157.4 ± 46.0 200.4 ± 53.13 Median (IQR) 70.0 (60.0 – 80.0) 160.0 (130.0 – 180.0) 210.0 (160.0 – 240.0) IQR: Inter quartile range SD: Standard deviation H: H for Kruskal Wallis test c 2 : Chi square test MC: Monte Carlo test p: p value for comparing different studied groups *: Statistically significant at p ≤ 0.05 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 18 Jan, 2025 Read the published version in Diagnostic Pathology → Version 1 posted Editorial decision: Revision requested 19 Dec, 2024 Reviews received at journal 04 Dec, 2024 Reviewers agreed at journal 25 Nov, 2024 Reviewers invited by journal 20 Nov, 2024 Editor assigned by journal 16 Jul, 2024 Submission checks completed at journal 16 Jul, 2024 First submitted to journal 15 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4744381","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":327863497,"identity":"8f45291c-7e32-4fd0-afdf-eab34bcd84d5","order_by":0,"name":"Menna Allah Shalaby","email":"data:image/png;base64,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","orcid":"","institution":"Menoufia University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Menna","middleName":"Allah","lastName":"Shalaby","suffix":""},{"id":327863498,"identity":"2c311cbd-401c-4776-ba9f-aee31aa5a81e","order_by":1,"name":"Marwa Dawoud","email":"","orcid":"","institution":"Menoufia University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marwa","middleName":"","lastName":"Dawoud","suffix":""},{"id":327863499,"identity":"cf5356dd-5218-43e0-baab-679de9320e64","order_by":2,"name":"Marwa Gadallah","email":"","orcid":"","institution":"Menoufia University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marwa","middleName":"","lastName":"Gadallah","suffix":""},{"id":327863500,"identity":"99846a40-f048-4414-bbed-1103e48e78fc","order_by":3,"name":"Asmaa Abdou","email":"","orcid":"","institution":"Menoufia University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Asmaa","middleName":"","lastName":"Abdou","suffix":""}],"badges":[],"createdAt":"2024-07-15 16:47:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4744381/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4744381/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13000-025-01598-2","type":"published","date":"2025-01-18T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62632140,"identity":"b6e8605f-dbe0-48f7-ae62-a6d862ad8237","added_by":"auto","created_at":"2024-08-16 16:09:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5911573,"visible":true,"origin":"","legend":"\u003cp\u003ePTHrP Immunostaining showed \u003cstrong\u003e(A)\u003c/strong\u003e Low cytoplasmic expression in normal breast lobules. \u003cstrong\u003e(B)\u003c/strong\u003e Moderate cytoplasmic expression in ductal carcinoma in situ (DCIS). \u003cstrong\u003e(C)\u003c/strong\u003e Strong cytoplasmic expression in invasive breast carcinoma (IBC) (IHC x200).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/e2b0be89672978609bf7f0dc.png"},{"id":62631113,"identity":"43b3545d-6a9d-4204-ab96-8aef16ad2ed3","added_by":"auto","created_at":"2024-08-16 16:01:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":381258,"visible":true,"origin":"","legend":"\u003cp\u003eHigh PTHrP percent of expression was significantly associated with (\u003cstrong\u003eA)\u003c/strong\u003emetastasis (p = 0.009), (\u003cstrong\u003eB)\u003c/strong\u003e bone metastasis (p = 0.012) and (\u003cstrong\u003eC)\u003c/strong\u003elymphovascular invasion (p = 0.037).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/3cdc5c818099cfab11c26ae8.png"},{"id":62632992,"identity":"dc462321-62eb-4ecc-b7fe-6a0811a44189","added_by":"auto","created_at":"2024-08-16 16:17:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":304972,"visible":true,"origin":"","legend":"\u003cp\u003eHigh PTHrP H score values were significantly associated with (\u003cstrong\u003eA)\u003c/strong\u003e postmenopausal status (p = 0.044), (\u003cstrong\u003eB) \u003c/strong\u003epresence of metastasis (p = 0.007), (\u003cstrong\u003eC)\u003c/strong\u003e luminal subtype (p = 0.038), (\u003cstrong\u003eD)\u003c/strong\u003e ER positivity (p = 0.032), and (\u003cstrong\u003eE)\u003c/strong\u003e PR positivity (p = 0.005).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/4f32b6556e1d62fe86bdd9f1.png"},{"id":62631117,"identity":"be46bff6-29bd-44c9-8a13-62385933ce9c","added_by":"auto","created_at":"2024-08-16 16:01:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":8109048,"visible":true,"origin":"","legend":"\u003cp\u003eEzrin Immunostaining showed \u003cstrong\u003e(A)\u003c/strong\u003e apical expression in normal breast lobules. \u003cstrong\u003e(B)\u003c/strong\u003e Ductal carcinoma in situ (DCIS) exhibited strong cytoplasmic expression of ezrin.\u003cstrong\u003e (C)\u003c/strong\u003e Invasive breast carcinoma (IBC) demonstrated moderate cytoplasmic expression of ezrin. \u003cstrong\u003e(D)\u003c/strong\u003eInvasive breast carcinoma (IBC) exhibited strong cytoplasmic expression of ezrin (IHC x200).\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/5a432db56c8024e5a3d316e6.png"},{"id":62632138,"identity":"e844aa1a-5d69-4792-8686-e3e0d16caad4","added_by":"auto","created_at":"2024-08-16 16:09:19","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":409052,"visible":true,"origin":"","legend":"\u003cp\u003eHigh ezrin H score values were significantly associated with (\u003cstrong\u003eA)\u003c/strong\u003e high tumor grade (p=0.002), \u003cstrong\u003e(B)\u003c/strong\u003e high N stage (p=0.045), \u003cstrong\u003e(C) \u003c/strong\u003eadvanced AJCC stage (p=0.043), \u003cstrong\u003e(D)\u003c/strong\u003e presence of metastasis (p=0.001), \u003cstrong\u003e(E)\u003c/strong\u003e high grade of DCIS (p=0.033), \u003cstrong\u003e(F)\u003c/strong\u003e extensive DCIS (0.007), and \u003cstrong\u003e(G)\u003c/strong\u003e perineural invasion (p=0.031).\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/39bbf3687540198ab86d32e0.png"},{"id":62631111,"identity":"1adb724f-4234-48c3-869d-462da5975952","added_by":"auto","created_at":"2024-08-16 16:01:19","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":310961,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlation between ezrin H score and \u003cstrong\u003e(A)\u003c/strong\u003e high mitosis and \u003cstrong\u003e(B) \u003c/strong\u003ehigh\u003cstrong\u003e \u003c/strong\u003eNPI score.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/bcc7f64fadd0ec1f9873bd18.png"},{"id":62632991,"identity":"dbb19c6c-95f1-4756-86f8-13dbd965fb36","added_by":"auto","created_at":"2024-08-16 16:17:19","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":289088,"visible":true,"origin":"","legend":"\u003cp\u003eThe\u003cstrong\u003e \u003c/strong\u003ecorrelation between PTHrP and ezrin regarding \u003cstrong\u003e(A)\u003c/strong\u003e percent and \u003cstrong\u003e(B) \u003c/strong\u003eH score.\u003c/p\u003e","description":"","filename":"Figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/23446c792f677cd4658b4c11.png"},{"id":62631119,"identity":"1b967104-a78d-4a87-959a-8ca6189bcaff","added_by":"auto","created_at":"2024-08-16 16:01:20","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":226595,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate analysis of studied markers revealed prolonged OS with\u003cstrong\u003e (A) \u003c/strong\u003emoderate intensity of ezrin (p = 0.007) and \u003cstrong\u003e(B)\u003c/strong\u003e low ezrin H score (p = 0.002).\u003c/p\u003e","description":"","filename":"Figure8.png","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/a30f4419db947fd72a0b388b.png"},{"id":74284736,"identity":"e238e603-7e02-4389-a00c-eb04a4cac647","added_by":"auto","created_at":"2025-01-20 16:12:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":22806550,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4744381/v1/fb1a23be-d273-43bb-b337-55ba5bb6ffff.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Immunohistochemical expression of Parathyroid hormone-related protein and Ezrin in Invasive Breast Carcinoma of No Special Type: A retrospective Analysis","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eBreast cancer remains one of the most common cancers globally, as reported by the GLOBOCAN 2020 data, ranking as the fifth leading cause of cancer-related mortality, with approximately 2.3\u0026nbsp;million new cases diagnosed annually (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In Egypt, the incidence of breast cancer is somewhat lower compared to the USA and Western nations, yet the mortality rate among Egyptian patients is notably higher (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInvasive breast carcinoma of no special type (IBC-NST) is the most frequently occurring among the different types of breast cancer, yet it presents a heterogeneous group with variable prognoses driven by diverse molecular characteristics that are not yet fully understood (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Identifying reliable biomarkers that predict therapeutic response and clinical outcome is crucial as treatment paradigms evolve.\u003c/p\u003e \u003cp\u003eDespite advances in early detection and management, the persistent issues of recurrence, metastasis, and therapeutic resistance underscore the imperative of advancing our understanding of the underlying molecular drivers of breast cancer (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In this context, exploring the role of key molecular markers such as parathyroid hormone-related protein (PTHrP) and ezrin offers promising pathways. PTHrP and ezrin have emerged as potentially significant biomarkers in several cancers, including breast cancer (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eParathyroid hormone-related protein (PTHrP) is synthesized in both normal breast tissue and breast cancer cells, where it induces bone destruction when secreted by cancer cells metastasized to the bone. Upon release, PTHrP interacts with its receptor on adjacent bone cells. However, in the context of breast cancer, PTHrP does not follow this binding mechanism. Instead, it travels within the cells, exerting either tumor-promoting or tumor-suppressing effects (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSimilarly, ezrin, a protein belonging to the ezrin-radixin-moesin (ERM) family, is pivotal in metastasis. It connects the cytoskeleton to the plasma membrane, thereby affecting cell adhesion, mobility, and the signaling pathways essential for tumor progression and regulation of tumor metastasis in several cancers, including breast cancer (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSome studies suggest that both PTHrP and ezrin are not only overexpressed in various malignancies but also correlate with poor prognostic outcomes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). However, their expression and prognostic value, specifically in IBC-NST, remain underexplored. This gap in knowledge presents a significant limitation for the stratification of patients and the tailoring of therapeutic strategies.\u003c/p\u003e \u003cp\u003eInterestingly, the interplay between PTHrP and ezrin in breast cancer has not been previously explored. This study investigates the interaction between PTHrP and ezrin within the specific setting of IBC-NST. By evaluating their immunohistochemical expression and correlation, this research aims to clarify their prognostic value in breast cancer.\u003c/p\u003e"},{"header":"2 Patients and Methods","content":"\u003cp\u003eThis retrospective analysis was conducted on 160 archival paraffin-embedded tissue blocks collected from patients diagnosed with IBC-NST and normal breast tissue at the Menoufia University Hospital, Pathology Department, during the period from January 2018 to January 2022. Ethical clearance for this study was obtained from the Institutional Review Board (IRB) under code no (3/2022PATHO33).\u003c/p\u003e \u003cp\u003eThe study group was divided into 123 cases of IBC-NST, treated primarily by modified radical mastectomy in 103 cases and conservative breast surgery in 20 cases, and 37 control cases comprising normal breast tissue samples obtained from reduction mammoplasty. Exclusion criteria included prior neoadjuvant therapy, other histological types rather than IBC-NST, and core biopsy specimens.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Clinicopathological data\u003c/h2\u003e \u003cp\u003eClinicopathological data were gathered from medical records. Histopathological evaluations were performed on sections stained with hematoxylin and eosin. Tumor staging adhered to the most recent TNM classification guidelines set by the American Joint Committee on Cancer (AJCC) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Tumors were categorized into early-stage (T1 and T2) and advanced-stage (T3 and T4). Grading was conducted using the Elston and Ellis grading system (1991) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and the Nottingham Prognostic Index was assessed (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), the presence and extent of DCIS and perineural as well as lymphovascular invasion were evaluated​​​​ (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Mitotic figures were quantified as described by Lehr et al. (2012) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The molecular classification was determined based on the immunostaining results for ER, PR, Her2neu, and Ki67 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Tissue microarray (TMA) blocks\u003c/h2\u003e \u003cp\u003eFor immunohistochemical analysis, tissue microarrays (TMAs) were created using a manual tissue arrayer (Breecher Instrument Manual Microarray, Wisconsin, USA). Each TMA block contained duplicate cores from each tissue sample, ensuring adequate sampling.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Immunohistochemical analysis\u003c/h2\u003e \u003cp\u003eThe primary antibodies employed included a mouse monoclonal antibody for PTHrP (concentrated at 100 \u0026micro;l with a 1:100 dilution, Chongqing Biospes, Catalog # YMA1281) and a rabbit polyclonal antibody for ezrin (concentrated at 100 \u0026micro;l with a 1:150 dilution, ABclonal, Catalog # A19048), following an overnight incubation at dilutions recommended by the manufacturers. Standardized protocols using tris-EDTA buffer were employed for antigen retrieval, with specific controls (normal kidney for PTHrP and colon carcinoma for ezrin) in place for each staining batch ​(\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eQuantitative and qualitative assessments of immunohistochemical staining were systematically performed, evaluating both the staining patterns and intensities across samples. The semiquantitative H-score was utilized to integrate the proportion and intensity of staining, providing a composite expression score for each marker (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Survival Data Analysis\u003c/h2\u003e \u003cp\u003eSurvival analyses utilized data from Menoufia University's Clinical Oncology and Nuclear Medicine Department, spanning a follow-up period from January 2018 to January 2022. Kaplan-Meier and Hazard function curves were constructed to illustrate survival trends and associations (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e \u003cp\u003eThe data were managed and analyzed using IBM SPSS software version 20.0. (Armonk, NY: IBM Corp). Continuous data were reported as means and standard deviations (SD), whereas categorical data were represented as frequencies and percentages. Depending on suitability, categorical variables were compared using the Chi-square or Monto-Carlo tests. The Student's t-test was applied for normally distributed quantitative variables, whereas the Kruskal-Wallis test was used for non-normally distributed quantitative variables. Survival analysis was conducted using the Kaplan-Meier method. The Cox proportional hazards model was used to identify independent prognostic factors. A p-value below 0.05 was deemed statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Clinicopathological Data of Breast Cancer Cases\u003c/h2\u003e \u003cp\u003eThe clinicopathological characteristics of the studied cases are detailed in Table\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Immunohistochemical Expression of PTHrP in the Studied Groups\u003c/h2\u003e \u003cp\u003ePTHrP was expressed in all investigated cases, either benign or malignant, as a cytoplasmic pattern of expression. There was a significant progressive increase in the percent of PTHrP expression from normal breast (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of 64.86\u0026thinsp;\u0026plusmn;\u0026thinsp;11.58, median of 65.0) to adjacent DCIS lesions (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of 68.06\u0026thinsp;\u0026plusmn;\u0026thinsp;7.92, median of 65.0) peaking in IBC-NST cases (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of 80.53\u0026thinsp;\u0026plusmn;\u0026thinsp;8.91, median of 80.0) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, there was a progressive increase in PTHrP H score values from normal breast (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD 97.97\u0026thinsp;\u0026plusmn;\u0026thinsp;37.18, median of 80.0) to adjacent DCIS lesions (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD 186.5\u0026thinsp;\u0026plusmn;\u0026thinsp;36.77, median of 195.0) peaking in IBC-NST cases (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD 209.51\u0026thinsp;\u0026plusmn;\u0026thinsp;49.86, median of 210.0) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). (Table\u0026nbsp;2 and Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Relationship Between PTHrP Expression and Clinicopathological Data in Breast Cancer Tissues\u003c/h2\u003e \u003cp\u003eIn IBC cases, high PTHrP percent expression was significantly associated with the presence of metastasis (p\u0026thinsp;=\u0026thinsp;0.009), bone metastasis (p\u0026thinsp;=\u0026thinsp;0.012), and lymphovascular invasion (p\u0026thinsp;=\u0026thinsp;0.037) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e). High PTHrP H score values were significantly associated with postmenopausal status (p\u0026thinsp;=\u0026thinsp;0.044), presence of metastasis (p\u0026thinsp;=\u0026thinsp;0.007), luminal subtype (p\u0026thinsp;=\u0026thinsp;0.038), ER positivity (p\u0026thinsp;=\u0026thinsp;0.032), and PR positivity (p\u0026thinsp;=\u0026thinsp;0.005) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Immunohistochemical Expression of Ezrin in the Studied Groups\u003c/h2\u003e \u003cp\u003eEzrin was expressed in 59.5% of the control group, all adjacent DCIS lesions, and 92.7% of the IBC-NST group as a cytoplasmic pattern of expression. There was a significant progressive increase in the percent of ezrin expression from the normal breast (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of 67.05\u0026thinsp;\u0026plusmn;\u0026thinsp;8.95, median of 70.0) to adjacent DCIS lesions (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of 67.74\u0026thinsp;\u0026plusmn;\u0026thinsp;8.25, median of 70.0) peaking in IBC-NST cases (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD of 79.25\u0026thinsp;\u0026plusmn;\u0026thinsp;8.15, median of 80.0) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, there was a progressive increase in ezrin H score values from normal breast (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD 75.23\u0026thinsp;\u0026plusmn;\u0026thinsp;22.70, median of 70.0) to adjacent DCIS lesions (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD 157.4\u0026thinsp;\u0026plusmn;\u0026thinsp;46.0, median of 160.0) peaking in IBC-NST cases (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD 200.4\u0026thinsp;\u0026plusmn;\u0026thinsp;53.13, median of 210.0) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). (Table\u0026nbsp;3 and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Relationship Between Ezrin Expression and Clinicopathological Data in Breast Cancer Tissues\u003c/h2\u003e \u003cp\u003eIn IBC cases, elevated ezrin H score values were notably linked to high tumor grade (p\u0026thinsp;=\u0026thinsp;0.002), high N stage (p\u0026thinsp;=\u0026thinsp;0.045), advanced AJCC stage grouping (p\u0026thinsp;=\u0026thinsp;0.043), presence of metastasis (p\u0026thinsp;=\u0026thinsp;0.001), higher grade (p\u0026thinsp;=\u0026thinsp;0.033), and a greater extent of DCIS and perineural invasion (p\u0026thinsp;=\u0026thinsp;0.031) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Additionally, there was a significant positive correlation between elevated ezrin H score and both increased mitotic activity (p\u0026thinsp;=\u0026thinsp;0.002) and higher NPI score (p\u0026thinsp;=\u0026thinsp;0.003) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Relationship Between PTHrP and Ezrin Expression in Breast Cancer Tissues\u003c/h2\u003e \u003cp\u003eA highly significant direct correlation was observed between PTHrP and ezrin expression regarding percent (rs\u0026thinsp;=\u0026thinsp;0.238, p\u0026thinsp;=\u0026thinsp;0.011) and H score values (rs\u0026thinsp;=\u0026thinsp;0.341, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Overall Survival Analysis\u003c/h2\u003e \u003cp\u003eOverall survival data were available for 94 cases (76.4%). The follow-up period extended from January 2018 to December 2022, with survival time ranging from 9 to 52 months (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD: 30.15\u0026thinsp;\u0026plusmn;\u0026thinsp;11.25 months, median: 30 months). During this period, 29 patients (23.6%) died of their disease. Prolonged overall survival was associated with moderate intensity (p\u0026thinsp;=\u0026thinsp;0.007) and Low H score values (p\u0026thinsp;=\u0026thinsp;0.002) of ezrin (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e8\u003c/span\u003e). However, the Multivariate Cox regression analysis showed no significant ezrin expression independence in breast cancer patients' overall survival.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eParathyroid hormone-related protein (PTHrP) is a recognized factor in breast cancer pathogenesis, particularly concerning bone metastasis (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The results of the current study revealed that PTHrP expression was significantly elevated in IBC cases compared to adjacent DCIS lesions and normal breast tissues. This finding aligns with previous studies that have shown elevated PTHrP levels in more aggressive breast cancer subtypes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)​​​​. Specifically, PTHrP expression in the present study was associated with poor prognostic factors such as lymphovascular invasion, metastasis, and bone metastasis. These findings align with those of Yoshida et al. (2000) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), who observed that elevated PTHrP expression is associated with the progression of breast tumors, the development of bone metastases, and reduced overall patient survival. Additionally, Powell et al. (1991) (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) reported a higher prevalence of PTHrP expression in breast cancer bone metastases compared to other metastatic sites.\u003c/p\u003e \u003cp\u003ePTHrP has been shown to promote angiogenesis at skeletal metastasis sites, which may aid in tumor cell spread, colonization, and growth (\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e–\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Its enhancement of various angiogenic factors, such as IL-6, IL-8, CXCL1, and CCL2/MCP-1, likely contributes to the development and progression of tumors that produce PTHrP.\u003c/p\u003e \u003cp\u003eAn additional explanation for PTHrP's role in bone metastasis comes from an experimental model using the estrogen receptor-positive human MCF7 breast cancer cell line. These cells stayed dormant in bone after being injected into nude mice but started to aggressively colonize bone and form lytic deposits when PTHrP was overexpressed (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Gene expression analysis indicated that overexpression of PTHrP led to the downregulation of several pro-dormancy genes. This included LIFR and its downstream signaling target, SOCS3 (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur study also found a significant association between high PTHrP H score values and positive hormone receptor status (ER and PR), luminal subtype, and postmenopausal status. These findings are in line with the work of Henderson et al. (2001) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) who reported that PTHrP expression was correlated with ER and PR positivity and better differentiation in breast cancer tissues. On the other hand, the study's high PTHrP levels in primary tumors were associated with reduced bone metastases and better prognosis​​. This discrepancy might be due to differences in study populations or methodologies, highlighting the complexity of PTHrP's role in breast cancer progression.\u003c/p\u003e \u003cp\u003eIn literature, some studies (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) reported that ER positivity was linked to a higher incidence and increased risk of bone metastasis. Another study connected PTHrP with ER and discovered that the expression of ER, OPNcyt, and PTHrPR1 proteins in primary breast cancers might be linked to a higher risk of bone metastasis (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Other studies (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) reported that the luminal subtype was identified as the most prevalent phenotype among patients with bone metastasis.\u003c/p\u003e \u003cp\u003eThe role of PTHrP in breast cancer remains complex, with its expression being influenced by various factors, including its actions on parathyroid hormone receptor (PTHR) and stage of tumorigenesis, which may affect its prognostic significance (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding Ezrin expression, the results of this study revealed that it was significantly upregulated in IBC cases compared to adjacent DCIS lesions and normal tissues. High ezrin expression was associated with poor prognostic factors such as advanced AJCC stage, higher tumor grade, advanced N stage, and presence of metastasis and perineural invasion​​. These results align with the work of Ma et al. (2008) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), who reported that increased ezrin expression was positively correlated with lymph node involvement, indicating that ezrin may serve as a biomarker for predicting lymphatic metastasis in breast carcinoma. Moreover, Xu et al. (2014) discovered that ezrin expression was linked to lymph node involvement and a high histological grade, corroborating our findings (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur study further showed that ezrin expression was significantly correlated with higher mitotic activity and NPI score, indicating that higher ezrin levels are associated with more aggressive tumor behavior. These findings are consistent with previous reports demonstrating a link between ezrin overexpression and increased metastatic potential in various cancer types (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe relocation of ezrin from the apical membrane in normal breast epithelial cells to the cytoplasm in invasive breast cancer cells suggests a functional role of ezrin in promoting tumor invasion and metastasis (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Ezrin is believed to facilitate breast cancer cell migration and invasion through the induction of EMT. Studies have demonstrated that silencing ezrin results in breast cancer cells adopting an epithelial morphology and losing their migratory ability. In contrast, overexpression of ezrin leads to a dispersed, spindle-shaped morphology. Additionally, ezrin-depleted cells exhibited higher levels of epithelial markers (E-cadherin and ZO-1) and lower levels of Vimentin, Snail, Slug, and MMP9, whereas the opposite pattern was observed in cells with ezrin overexpression (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsidering the significance of angiogenesis in cancer metastasis and progression (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), the role ezrin plays in breast cancer angiogenesis was previously investigated, and it was found that vascular mimicry and the microtubule formation ability of HUVECs decreased in cells with ezrin depletion but increased in cells with ezrin overexpression. Further Western blot analysis showed that silencing ezrin reduced the expression levels of VEGF and HIF1α, while overexpression of ezrin increased these levels, indicating that ezrin may possess pro-angiogenic properties in breast cancer (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eKaplan-Meier survival analysis in our study indicated that higher ezrin expression, both in terms of intensity and H score, was associated with poorer prognosis and reduced overall survival in breast cancer patients. These findings are supported by previous studies that have demonstrated the prognostic value of ezrin in predicting poor outcomes in breast cancer\u003cb\u003e​​\u003c/b\u003e (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur study revealed a significant correlation between PTHrP and ezrin expression in breast cancer tissues. Elevated ezrin levels were found to correlate with increased PTHrP levels, indicating a possible interaction or joint regulation between these proteins. This co-expression could contribute to tumor growth and metastasis, thereby serving as important prognostic biomarkers and potential therapeutic targets in breast cancer therapy. Although the relationship between PTHrP and ezrin has not been extensively studied in breast cancer, similar interactions have been observed in other cancers, such as lung cancer bone metastases, where TGF-β induced both ezrin and PTHrP expression, facilitating tumor growth (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e)​​​​.\u003c/p\u003e \u003cp\u003eThe co-expression of PTHrP and ezrin may indicate a synergistic role in enhancing breast cancer cells' invasive and metastatic potential. Further research is needed to elucidate the underlying mechanisms of their interaction and their combined impact on breast cancer progression. Understanding these pathways could lead to developing novel therapeutic strategies targeting both proteins to inhibit metastasis and improve patient outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations of the study\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis study has some limitations, including a relatively small sample size and a short follow-up duration, which may affect the generalizability of the results. Additionally, data on patient response to therapy prevents a comprehensive assessment of the therapeutic implications of PTHrP and ezrin expression.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eOur findings highlight the significant roles of PTHrP and ezrin in breast cancer progression and prognosis. Elevated expression levels of these proteins are associated with more aggressive disease. These biomarkers can potentially serve as valuable prognostic tools and therapeutic targets in breast cancer. Further studies are needed to fully understand the mechanisms underlying their co-regulation and their implications in breast cancer metastasis and treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eAJCC\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Joint Committee on Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDCIS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDuctal Carcinoma In situ\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eERM\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEzrin-Radixin-Moesin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eIBC-NST\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einvasive breast carcinoma of no special type\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eOS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePTHrP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eParathyroid hormone-related protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTILs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTumour-infiltrating lymphocytes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eTMAs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etissue microarrays\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interests:\u003c/strong\u003e no conflict of interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from public, commercial, or not-for-profit funding agencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed equally to this manuscript. Menna Allah G. Shalaby and Asmaa G. Abdou designed and conceptualized the study and managed data preparation. All authors prepared the tissue microarray slides. Marwa M. Dawoud and Marwa S. Gadallah performed the statistical analysis and prepared the figures. All authors drafted the original paper. All authors revised the manuscript for intellectual content and read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMenna Allah Gamil Ali Shalaby.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective analysis study received approval from the Institutional Review Board at The Faculty of Medicine and Menoufia University Hospitals, Menoufia University, Egypt (Ethical Code: 3/2022PATHO33). Patient consent was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent\u003c/strong\u003e \u003cstrong\u003efor publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available from the corresponding author upon request. Researchers interested in accessing the data are encouraged to contact the corresponding author to discuss the conditions under which access may be granted\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al. 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Cancer Sci [Internet]. 2018;109(5):1627\u0026ndash;37. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://onlinelibrary.wiley.com/doi/\u003c/span\u003e\u003cspan address=\"https://onlinelibrary.wiley.com/doi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/cas.13570\u003c/span\u003e\u003cspan address=\"10.1111/cas.13570\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeng X, Tannehill-Gregg SH, Nadella MVP, He G, Levine A, Cao Y et al. Parathyroid hormone-related protein and ezrin are up-regulated in human lung cancer bone metastases. Clin Exp Metastasis [Internet]. 2007;24(2):107\u0026ndash;19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://link.springer.com/\u003c/span\u003e\u003cspan address=\"https://link.springer.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10585-007-9059-9\u003c/span\u003e\u003cspan address=\"10.1007/s10585-007-9059-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable (1):\u0026nbsp;\u003c/strong\u003eClinicopathological data of the studied breast cancer cases (n=123).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical pathology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003e\u0026lt;50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e31.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003e\u0026ge;50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e68.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e30.0 \u0026ndash; 82.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e55.05 \u0026plusmn; 11.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e55.0 (47.0\u0026ndash;65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMenopausal status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003ePremenopausal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e44.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003ePostmenopausal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e55.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultifocality\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eUnifocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e85.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMultifocal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e14.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e83.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e14.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.75529865125241%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eSize\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.15028901734104%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.094412331406552%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e0.50 \u0026ndash; 15.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e3.73 \u0026plusmn; 2.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e3.50 (2.0\u0026ndash;5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eT stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e30.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e45.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e19.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eT4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eT stage grouping\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eEarly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e75.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eAdvanced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e24.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eN stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eN0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e22.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e23.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eN2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e27.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eN3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e26.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eNodal metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e22.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e78.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAJCC stage grouping\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eEarly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e45.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eAdvanced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e54.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e89.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eBone metastasis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e94.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eInsitu status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e74.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e25.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade of DCIS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eLow grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eHigh grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eDCIS Percent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNon extensive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eExtensive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e13.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.75529865125241%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eMitosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.15028901734104%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.094412331406552%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e1.0 \u0026ndash; 23.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e3.87 \u0026plusmn; 5.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e2.0 (1.0\u0026ndash;3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPI group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eGood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e14.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e39.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003ePoor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e45.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.75529865125241%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPI score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.15028901734104%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.094412331406552%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e2.40 \u0026ndash; 8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e5.15 \u0026plusmn; 1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.73352435530086%\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.26647564469914%\" colspan=\"2\" style=\"width: 45.6522%;\"\u003e\n \u003cp\u003e5.30 (4.20\u0026ndash;6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eTIL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e61.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e21.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eDense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e115\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e93.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePNI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e92.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eMolecular subtype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eLuminal\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e78.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eTriple negative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e8.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eHer2neu enriched\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e13.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eER\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e21.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e78.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e30.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e69.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eHer2neu\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e61.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e39.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.69230769230769%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eKi 67 proliferative index\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.07692307692308%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eLow proliferative index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.615384615384615%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e56.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"56.57142857142857%\" valign=\"top\" style=\"width: 22.7536%;\"\u003e\n \u003cp\u003eHigh proliferative index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 19.2776%;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.714285714285715%\" valign=\"top\" style=\"width: 25.6499%;\"\u003e\n \u003cp\u003e43.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable (2):\u0026nbsp;\u003c/strong\u003eComparison of PTHrP expression in different studied groups.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"529\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.312617702448211%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePTHrP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.715630885122412%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003cbr\u003e\u0026nbsp;(n = 37)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjacent DCIS\u0026nbsp;\u003cbr\u003e\u0026nbsp;(n= 31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eIBC\u003cbr\u003e\u0026nbsp;(n = 123)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.559322033898304%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTest of Sig.\u003cbr\u003e (p\u003csub\u003e)\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.312617702448211%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003ePercent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.715630885122412%\" valign=\"top\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\"\u003e\n \u003cp\u003e40.0 \u0026ndash; 85.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\"\u003e\n \u003cp\u003e60.0 \u0026ndash; 90.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\"\u003e\n \u003cp\u003e60.0 \u0026ndash; 95.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.559322033898304%\" rowspan=\"3\"\u003e\n \u003cp\u003eH(p)=\u003cbr\u003e64.716\u003csup\u003e*\u003c/sup\u003e\u003cbr\u003e(\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.720626631853786%\" valign=\"top\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e64.86 \u0026plusmn; 11.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e68.06 \u0026plusmn; 7.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e80.53 \u0026plusmn; 8.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.720626631853786%\" valign=\"top\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e65.0\u003cbr\u003e\u0026nbsp;(60.0 \u0026ndash; 70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e65.0\u003cbr\u003e\u0026nbsp; (60.0 \u0026ndash; 70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e80.0\u0026nbsp;\u003cbr\u003e\u0026nbsp;(70.0 \u0026ndash; 90.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.312617702448211%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;H score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.715630885122412%\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\"\u003e\n \u003cp\u003e50.0 \u0026ndash; 170.0 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\"\u003e\n \u003cp\u003e120.0 \u0026ndash; 270.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.137476459510356%\" colspan=\"2\"\u003e\n \u003cp\u003e70.0 \u0026ndash; 270.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.559322033898304%\" rowspan=\"3\"\u003e\n \u003cp\u003eH(p)=\u003cbr\u003e77.737\u003csup\u003e*\u003c/sup\u003e\u003cbr\u003e(\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.720626631853786%\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e97.97 \u0026plusmn; 37.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e186.5 \u0026plusmn; 36.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e209.51 \u0026plusmn; 49.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.720626631853786%\"\u003e\n \u003cp\u003eMedian\u003cbr\u003e\u0026nbsp; (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e80.0\u003cbr\u003e\u0026nbsp;(70.0 \u0026ndash; 120.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e195.0\u0026nbsp;\u003cbr\u003e\u0026nbsp;(170.0 \u0026ndash; 210.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.759791122715406%\" colspan=\"2\"\u003e\n \u003cp\u003e210.0\u003cbr\u003e\u0026nbsp;(180.0 \u0026ndash; 255.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIQR:\u003cstrong\u003e\u0026nbsp;Inter quartile range\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;SD: \u003cstrong\u003eStandard deviation\u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;H: H for Kruskal Wallis test\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ep: p value for comparing different studied groups\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e*: Statistically significant at p \u0026le; 0.05\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable (3):\u0026nbsp;\u003c/strong\u003eComparison of ezrin expression in different studied groups.\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"522\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.869980879541108%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eEzrin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.164435946462714%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003cbr\u003e\u0026nbsp;(n = 37)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjacent DCIS\u0026nbsp;\u003cbr\u003e\u0026nbsp;(n= 31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eIBC\u003cbr\u003e\u0026nbsp;(n = 123)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.766730401529637%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTest of Sig.\u003cbr\u003e\u0026nbsp;(p)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.961538461538462%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eExpression\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26923076923077%\"\u003e\n \u003cp\u003eNegative\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.653846153846153%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.653846153846153%\"\u003e\n \u003cp\u003e40.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.653846153846153%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.653846153846153%\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.653846153846153%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.653846153846153%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.846153846153847%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e=\u003cbr\u003e27.323\u003csup\u003e*\u003c/sup\u003e\u003cbr\u003e(\u003csup\u003eMC\u003c/sup\u003ep\u003cbr\u003e(\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.027397260273972%\"\u003e\n \u003cp\u003ePositive\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32876712328767%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32876712328767%\"\u003e\n \u003cp\u003e59.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32876712328767%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32876712328767%\"\u003e\n \u003cp\u003e100.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32876712328767%\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32876712328767%\"\u003e\n \u003cp\u003e92.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.869980879541108%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003ePercent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.164435946462714%\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e45.0 \u0026ndash; 80.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e60.0 \u0026ndash; 90.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e60.0 \u0026ndash; 90.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.766730401529637%\" rowspan=\"3\"\u003e\n \u003cp\u003eH=\u003cbr\u003e48.930\u003csup\u003e*\u003c/sup\u003e\u003cbr\u003e(\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.815217391304348%\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e67.05 \u0026plusmn; 8.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e67.74 \u0026plusmn; 8.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e79.25 \u0026plusmn; 8.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.815217391304348%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e70.0\u003cbr\u003e\u0026nbsp;(60.0 \u0026ndash; 75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e70.0\u0026nbsp;\u003cbr\u003e\u0026nbsp;(60.0 \u0026ndash; 70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e80.0\u0026nbsp;\u003cbr\u003e\u0026nbsp;(70.0 \u0026ndash; 90.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.869980879541108%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eH score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.164435946462714%\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e55.0 \u0026ndash; 140.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e60.0 \u0026ndash; 240.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.399617590822178%\" colspan=\"2\"\u003e\n \u003cp\u003e70.0 \u0026ndash; 270.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.766730401529637%\" rowspan=\"3\"\u003e\n \u003cp\u003eH=\u003cbr\u003e61.786\u003csup\u003e*\u003c/sup\u003e\u003cbr\u003e(\u0026lt;0.001\u003csup\u003e*\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.815217391304348%\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e75.23 \u0026plusmn; 22.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e157.4 \u0026plusmn; 46.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e200.4 \u0026plusmn; 53.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.815217391304348%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e70.0\u003cbr\u003e\u0026nbsp;(60.0 \u0026ndash; 80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e160.0\u0026nbsp;\u003cbr\u003e\u0026nbsp;(130.0 \u0026ndash; 180.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.72826086956522%\" colspan=\"2\"\u003e\n \u003cp\u003e210.0\u003cbr\u003e\u0026nbsp;(160.0 \u0026ndash; 240.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIQR:\u003cstrong\u003e\u0026nbsp;Inter quartile range\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;SD: \u003cstrong\u003eStandard deviation\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;H: H for Kruskal Wallis test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ec\u003csup\u003e2\u003c/sup\u003e: \u0026nbsp;\u003cstrong\u003eChi square test\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;MC: \u003cstrong\u003eMonte Carlo test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ep: p value for comparing different studied groups\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e*: Statistically significant at p \u0026le; 0.05\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"diagnostic-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dpat","sideBox":"Learn more about [Diagnostic Pathology](http://diagnosticpathology.biomedcentral.com)","snPcode":"13000","submissionUrl":"https://submission.nature.com/new-submission/13000/3","title":"Diagnostic Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Breast carcinoma, Ezrin, Immunohistochemistry, Parathyroid hormone-related protein (PTHrP)","lastPublishedDoi":"10.21203/rs.3.rs-4744381/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4744381/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGlobally, breast cancer ranks among the most common malignancies and has a high mortality rate. Invasive breast carcinoma of no special type (IBC-NST) presents a heterogeneous group with variable prognosis. Identifying reliable biomarkers is crucial for improving treatment strategies and predicting outcomes. This study investigates the immunohistochemical expression of parathyroid hormone-related protein (PTHrP) and ezrin in IBC-NST and their correlation with clinicopathological features and overall survival.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study analyzed 160 paraffin-embedded tissue samples, including 123 IBC-NST and 37 normal breast tissues, collected from patients treated at Menoufia University Hospital during the period from January 2018 to January 2022. Immunohistochemical staining for PTHrP and ezrin was performed, and expression levels were quantified using the H score.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePTHrP expression was significantly higher in IBC-NST than in adjacent DCIS and normal tissues (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). High PTHrP percent of expression was associated with metastasis (p\u0026thinsp;=\u0026thinsp;0.009), bone metastasis (p\u0026thinsp;=\u0026thinsp;0.012), and lymphovascular invasion (p\u0026thinsp;=\u0026thinsp;0.037). Ezrin expression was also significantly elevated in IBC-NST, with higher H score values correlating with high tumor grade (p\u0026thinsp;=\u0026thinsp;0.002), high N stage (p\u0026thinsp;=\u0026thinsp;0.045), advanced AJCC stage grouping (p\u0026thinsp;=\u0026thinsp;0.0043) and metastasis (p\u0026thinsp;=\u0026thinsp;0.001). A significant positive correlation was observed between PTHrP and ezrin expression (rs\u0026thinsp;=\u0026thinsp;0.341, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Kaplan-Meier analysis showed that high ezrin expression, in terms of intensity (p\u0026thinsp;=\u0026thinsp;0.007) and H score (p\u0026thinsp;=\u0026thinsp;0.002), was linked to poorer survival.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study highlights the significant roles of PTHrP and ezrin in breast cancer progression. Elevated levels of these proteins are associated with more aggressive disease, suggesting their capability as prognostic indicators and treatment targets in breast cancer. Additional studies are required to investigate their interaction and collective influence on breast cancer metastasis and treatment.\u003c/p\u003e","manuscriptTitle":"Immunohistochemical expression of Parathyroid hormone-related protein and Ezrin in Invasive Breast Carcinoma of No Special Type: A retrospective Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-16 16:01:15","doi":"10.21203/rs.3.rs-4744381/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-19T19:57:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-04T14:37:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"13561942918378085257577215986710793446","date":"2024-11-25T14:14:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-20T13:58:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-16T07:32:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-16T07:15:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Diagnostic Pathology","date":"2024-07-15T16:46:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"diagnostic-pathology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dpat","sideBox":"Learn more about [Diagnostic Pathology](http://diagnosticpathology.biomedcentral.com)","snPcode":"13000","submissionUrl":"https://submission.nature.com/new-submission/13000/3","title":"Diagnostic Pathology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dbb63d7f-e30d-4dd0-bc98-99c87800207e","owner":[],"postedDate":"August 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-20T16:05:22+00:00","versionOfRecord":{"articleIdentity":"rs-4744381","link":"https://doi.org/10.1186/s13000-025-01598-2","journal":{"identity":"diagnostic-pathology","isVorOnly":false,"title":"Diagnostic Pathology"},"publishedOn":"2025-01-18 15:57:13","publishedOnDateReadable":"January 18th, 2025"},"versionCreatedAt":"2024-08-16 16:01:15","video":"","vorDoi":"10.1186/s13000-025-01598-2","vorDoiUrl":"https://doi.org/10.1186/s13000-025-01598-2","workflowStages":[]},"version":"v1","identity":"rs-4744381","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4744381","identity":"rs-4744381","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}