Distinct Immune Landscape and Gene Expression Profiles in Breast Cancer: Young vs. Non-Young Patients

Distinct Immune Landscape and Gene Expression Profiles in Breast Cancer: Young vs. Non-Young Patients | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Distinct Immune Landscape and Gene Expression Profiles in Breast Cancer: Young vs. Non-Young Patients Zijun Zhu, Chen Gao, Yongxin Li, Xiao Liang, Zhancai Ye, Xinlong Tao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5382194/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Breast cancer remains a prevalent malignancy worldwide, particularly affecting younger women more aggressively. Significant differences in clinical and biological characteristics exist between breast cancer with young patients (BCY) and breast cancer with non-young patients (BCNY). However, the role of the immune microenvironment in these differences is not fully understood. Methods Data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database were analyzed to compare tumor-infiltrating immune cells (TIICs) and gene expression between BCY and BCNY. The CIBERSORT algorithm was used to estimate the relative abundance of 22 immune cell types, and differentially expressed genes (DEGs) were identified using the "limma" package in R. Results The BCY group had a higher prevalence of M0 macrophages and activated dendritic cells, while the BCNY group exhibited greater infiltration of CD4 memory T cells, M2 macrophages, and neutrophils. Differential gene expression analysis identified 11 significantly expressed genes between the groups, with genes such as FDCSP and GABRP upregulated in the BCY group. GSEA revealed that pro-inflammatory pathways, such as cytokine-cytokine receptor interaction, were enriched in the BCY group, while pathways related to metabolism and extracellular matrix interactions were enriched in the BCNY group. Kaplan-Meier analysis demonstrated that high expression of certain genes, such as NAT1, CA12, and SRARP, was associated with better relapse-free survival. Conclusion BCY exhibit a distinct immune landscape characterized by higher levels of pro-inflammatory immune cells and pathways, contributing to a more aggressive disease profile. Breast cancer Young patients Immune microenvironment Tumor-infiltrating immune cells Gene expression Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Breast cancer remains one of the most prevalent malignancies affecting women globally. 1 According to recent data, it accounts for 11.6% of all new cancer diagnoses, making it the second most common cancer type worldwide. 1 Despite advances in treatment that have led to improvements in overall survival rates, breast cancer still contributes significantly to cancer-related mortality, responsible for 6.9% of all cancer deaths. 1 This high incidence emphasizes the need for further research in breast cancer. Significant differences in clinical characteristics and prognosis have been observed across different age groups of breast cancer patients. 2 , 3 Breast cancer with young patients (BCY), defined by clinical guidelines as those under 40 years of age, 4 , 5 often present with more aggressive clinical features and poorer prognoses. 2 , 3 In recent years, many studies have elucidated the reasons for poor outcomes in BCY, focusing primarily on clinicopathological, molecular, and genomic differences between BCY and breast cancer with non-young patients (BCNY), providing valuable insights into the unique biological behavior of breast cancer in BCY. 2 , 6 However, despite these advances, the role of the tumor microenvironment particularly tumour-infiltrating immune cells (TIICs) different age groups remains underexplored. TIICs plays a pivotal role in tumor progression, metastasis, and response to therapy. 7 – 10 Differences in the composition and functional states of these immune cells, as well as underlying gene expression profiles, may be critical factors contributing to the more aggressive nature and poorer prognosis of BCY. Nonetheless, research specifically comparing TIICs and gene expression between different age groups is notably absent. This study, therefore, aims to investigate the differences in immune cell infiltration and gene expression between BCY and BCNY, and to elucidate the implications of these differences for patient prognosis. By examining both immune cell infiltration across various molecular subtypes, we seek to identify key immunological characteristics that influence the prognosis of BCY, ultimately providing a theoretical foundation for the development of personalized therapeutic strategies. Methods Data Source The data for this study were sourced from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database, which is a comprehensive repository of genomic and clinical data on breast cancer patients. 11 The METABRIC database includes extensive information on patient demographics, tumor characteristics, treatment outcomes, and high-throughput molecular data, such as gene expression profiles. This study complies with the requirements for using the METABRIC databases, therefore no ethical committee approval was needed. Patient Selection To achieve the study's objective of comparing tumor-infiltrating immune cells (TIICs) between BCY and BCNY, we applied specific inclusion and exclusion criteria to select the appropriate patient cohorts. The inclusion criteria were: (1) patients diagnosed with primary breast cancer; (2) availability of detailed diagnostic age; (3) availability of transcriptomic sequencing data, allowing for comprehensive analysis of gene expression profiles and immune cell infiltration. The exclusion criteria were: (1) patients diagnosed at or above the age of 55 years, as these patients are outside the study's focus age groups; (2) patients without information on PAM50 subtypes or Claudin-low subtype, as this data is necessary for subgroup analysis. The final cohort was divided into two groups based on age: the BCY group (patients under 40 years of age) and the BCNY group (patients aged 40 to less than 55 years). This age-based stratification was guided by both clinical guidelines 4,5 . TIICs analysis To estimate the relative abundance of 22 TIICs types in breast cancer specimens, we employed the cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. 12 This computational tool is specifically designed to deconvolute complex gene expression data, allowing for the identification and quantification of immune cell populations within heterogeneous tissue samples. By leveraging normalized gene expression data, CIBERSORT provides a detailed profile of TIICs in each sample. In this analysis, we utilized the LM22 signature matrix, which includes 547 genes that serve as markers for 22 distinct immune cell types, 13 such as B cells, T cells, natural killer cells, macrophages, dendritic cells, eosinophils, and neutrophils. CIBERSORT applies Monte Carlo sampling to estimate p-values, which assess the confidence of the deconvolution results for each sample. In this study, only samples with a p -value < 0.05 were included in the final analysis to ensure the robustness and accuracy of the inferred immune cell proportions. 12 Differentially expressed genes (DEGs) and gene set enrichment analysis (GSEA) DEGs analysis was conducted using the "limma" package in R, which applies a linear model to assess expression differences. 14 Genes with an adjusted p-value 1 were considered significantly differentially expressed. Following this, GSEA was performed to identify biological pathways and processes enriched in the BCY versus BCNY groups. Kaplan-Meier (KM) curve generation based on DEGs To further explore the prognostic significance of DEGs, KM survival curves were generated using data from all breast cancer patients in the METABRIC database. Patients were stratified into high and low expression groups based on the median expression level of each differentially expressed gene. The log-rank test was used to compare survival outcomes between these groups, providing insights into the potential impact of these DEGs on relapse free survival (RFS). Statistical Analysis Statistical comparisons between groups were performed using Welch's two-sample t-test and Pearson’s chi-squared test, depending on the distribution of the data. For the TIICs data, the Wilcoxon rank-sum test was applied to assess the statistical significance of differences between the BCY and BCNY groups. To execute the CIBERSORT algorithm, the following essential R packages were required: "e1071", "parallel", and "preprocessCore". The LM22 signature matrix file ("LM22.txt") was obtained from the CIBERSORT website. Kaplan-Meier (KM) survival curves were generated using the "survival" package in R. All statistical analyses were conducted using R software (version 4.3.3), and p -values < 0.05 were considered statistically significant. Results 1. Patient Characteristics This study included 640 patients with breast cancer: 120 in the BCY group and 520 in the BCNY group. A data screening flow chart is provided in Figure 1, with detailed characteristics shown in Table 1. The BCY group had a higher proportion of patients diagnosed with invasive ductal carcinoma (IDC) at 92.5%, compared to 79.2% in the BCNY group. The BCY group had a higher prevalence of basal and claudin-low subtypes, with 29.2% and 18.3% of patients respectively, compared to 12.7% and 6.5% in the BCNY group. In contrast, the BCNY group had more luminal A and luminal B subtypes, with luminal A present in 42.3% of patients and luminal B in 25.8%, compared to 18.3% and 10.0% in the BCY group (p < 0.001). The BCY group also had a significantly higher proportion of grade 3 tumors (78.3% vs. 49.4%, p < 0.001), reflecting a more aggressive disease profile. The BCY group also had a significantly higher proportion of grade 3 tumors (78.3% vs. 49.4%, p < 0.001), reflecting a more aggressive disease profile. Hormone receptor negativity was more prevalent in the BCY group, with 62.5% of patients being estrogen receptor (ER) negative and 67.5% being progesterone receptor (PR) negative, compared to 36.2% and 42.5% in the BCNY group ( p < 0.001). Although the BCY group had a higher rate of human epidermal growth factor receptor 2 (HER2) positivity, this difference was not statistically significant ( p = 0.059). Chemotherapy was more frequently used in the BCY group (64.2% vs. 38.1, p < 0.001), whereas hormone therapy was more common in the BCNY group. Radiotherapy usage did not differ significantly between the groups (p = 0.300). 2. TIICs analysis The overall analysis of TIICs showed that the BCY group had lower infiltration levels of CD4 memory T cells, gamma delta T cells, resting NK cells, M2 macrophages, resting mast cells, and neutrophils when compared to the BCNY group ( p < 0.05). In contrast, the BCY group showed higher proportions of M0 macrophages and activated dendritic cells in Figure 2. Supplementary figures 1-6 further revealed the differences in TIICs in different subtypes of breast cancer between young and non-young patients. In the luminal A subtype, the BCY group demonstrated reduced infiltration of M2 macrophages and increased infiltration of activated dendritic cells. For the luminal B subtype, the BCY group exhibited lower levels of CD8 T cells, follicular helper T cells, and M1 macrophages, while showing higher levels of M2 macrophages. In the Her2-enriched subtype, the BCY group had decreased infiltration of gamma delta T cells but increased infiltration of activated dendritic cells. In the basal subtype, the BCY group exhibited reduced infiltration of M2 macrophages, with a higher prevalence of activated dendritic cells. The the normal subtype showed that the BCY group had lower levels of CD4 memory T cells and resting NK cells, accompanied by increased infiltration of monocytes. Lastly, in the claudin-low subtype, the BCY group demonstrated higher levels of regulatory T cells and activated dendritic cells. 3. DGEs analysis and survival analysis A total of 11 genes that were significantly differentially expressed between the two groups. FDCSP and GABRP were upregulated in the BCY group, while the following genes were upregulated in the BCNY group: FOXA1, ESR1, MLPH, NAT1, CA12, ANKRD30A, SRARP, TFF3, and PIP. The heatmap (Supplementary figure 7) and volcano plot (Supplementary figure 8) further illustrate these differences. In supplementary figure 9 that KM survival curves indicated that high expression of the genes FDCSP, NAT1, CA12, ANKRD30A, SRARP, ESR1 and PIP was significantly associated with greater RFS. FOXA1, GABRP, MLPH, and TFF3 did not show a statistically significant association with RFS in breast cancer, as shown in Supplementary figure 10. 4. Gene set enrichment analysis in BCY and BCNY Figure 3 showed that pathways such as cytokine cytokine receptor interaction, chemokine signaling pathway, natural killer cell mediated cytotoxicity, T cell receptor signaling pathway, toll like receptor signaling pathway, systemic lupus erythematosus, pyrimidine metabolism, progesterone mediated oocyte maturation, antigen processing and presentation, oocyte meiosis, nod like receptor signaling pathway, p53 signaling pathway, allograft rejection, graft versus host disease, primary immunodeficiency, cell cycle, proteasome, and DNA replication were significantly enriched in BCY group ( p < 0.05). In BCNY group, pathways such as tyrosine metabolism, drug metabolism cytochrome P450, EMC receptor interaction, hypertrophic cardiomyopathy, TGF beta signaling pathway, and focal adhesion were significantly enriched ( p < 0.05), as shown in Figure 4. Discussion This study revealed significant differences in immune cell infiltration and gene expression between BCY and BCNY. BCY patients had higher levels of M0 macrophages and activated dendritic cells, while M2 macrophages, CD4 memory T cells, and neutrophils were lower compared to BCNY patients. Immune infiltration patterns also varied across molecular subtypes within BCY. Differential gene expression analysis showed that FDCSP and GABRP were upregulated in BCY, whereas FOXA1, ESR1, and other genes were upregulated in BCNY. GSEA indicated that inflammation and immune-related pathways were enriched in BCY, while metabolism and ECM-related pathways were prominent in BCNY. The findings of this study align with, yet also diverge from, previous literature exploring the molecular characteristics of BCY. Existing research indicates that BCY often exhibit unique genomic signatures, higher frequencies of aggressive subtypes, and distinct gene expression patterns compared to BCNY. For instance, studies by Gómez-Flores-Ramos et al. have showed that BCY often present with lower mRNA expression of estrogen receptors and higher expression of proliferation markers such as HER2 and Ki67. Our study, however, highlighted significant differences in immune cell infiltration and gene expression profiles, emphasizing an immunological perspective that has not been extensively covered in these earlier genomic-focused analyses 15 . The enrichment of specific immune pathways and the differential expression of immune-related genes suggest that the immune landscape could be a key factor contributing to the poor prognosis observed in BCY. This distinct focus complements the genomic insights provided by other researchers and supports the need for a more integrated understanding of both the genetic and immune components of BCY. The observed differences in immune cell infiltration between BCY and BCNY have important clinical implications. The increased proportion of M0 macrophages and activated dendritic cells in BCY may contribute to the more aggressive tumor phenotype often observed in BCY. Several studies have reported an association between higher levels of M0 macrophages and poorer prognosis in breast cancer, suggesting that the higher prevalence of M0 macrophages in BCY may be a significant factor driving their aggressive disease course 16 – 18 . M0 macrophages are often considered a precursor state that can be influenced by the tumor microenvironment to promote tumor growth and metastasis, and their elevated levels in BCY may reflect a greater potential for tumor-promoting immune modulation. Furthermore, recent research has also linked higher levels of activated dendritic cells with poorer prognosis in triple-negative breast cancer 19 . This suggests that the increased presence of activated dendritic cells in BCY, particularly those with triple-negative subtypes, may contribute to a more aggressive tumor phenotype and reduced survival outcomes. Additionally, the lower levels of CD4 memory T cells and neutrophils in BCY could indicate impaired adaptive immune responses and decreased recruitment of innate immune cells, respectively, both of which may contribute to the poorer prognosis observed in this group. Several studies have reported that lower levels of CD4 memory T cells and neutrophils are associated with worse prognosis in breast cancer 20 – 22 , suggesting that their reduced presence in BCY may exacerbate disease progression and lead to unfavorable outcomes. Moreover, studies have shown that lower levels of resting mast cells are associated with poorer prognosis in breast cancer patients 23 – 25 . The reduced presence of resting mast cells in BCY might, therefore, be another contributing factor to the poorer prognosis in this group, as these cells play a role in modulating immune responses within the tumor microenvironment. These findings highlight the need for age-specific approaches to immunotherapy that take into account the unique immune landscape of BCY patients. Developing therapies that specifically address the distinct immunological features of young breast cancer patients may help improve survival outcomes. The differential gene expression observed between BCY and BCNY provides important insights into the biological underpinnings of the distinct tumor behaviors seen in these age groups. In the BCY group, the upregulation of FDCSP and GABRP genes suggests potential roles in tumor progression; however, our findings indicate a nuanced prognostic impact for these genes. FDCSP was found to be associated with better prognosis in our cohort 26 , despite other studies linking its upregulation with poor outcomes in breast cancer. This discrepancy may be due to differences in tumor subtype distributions, underlying genetic backgrounds, or variations in the tumor microenvironment. The exact role of FDCSP in breast cancer remains to be fully elucidated, but our results suggest it may have context-dependent functions, potentially playing a protective role under certain conditions by influencing immune cell interactions or inhibiting tumor-promoting pathways. On the other hand, GABRP has been previously reported to be associated with poor prognosis in breast cancer, did not show significant prognostic impact in our analysis when comparing high and low expression groups. It is also possible that the influence of GABRP on prognosis is subtype-specific, and further research focusing on different breast cancer subtypes may be needed to clarify its role. We found that the genes NAT1, CA12, ANKRD30A, SRARP, and PIP were downregulated in BCY compared to BCNY, and their lower expression was associated with poorer RFS. This finding is consistent with other studies reporting that lower expression of these genes is linked to worse prognosis in breast cancer 27 , 28 . NAT1, an enzyme involved in acetylation, has been associated with DNA repair and cellular homeostasis, and its reduced expression may compromise these processes, leading to a more aggressive tumor phenotype 29 . CA12, a carbonic anhydrase, plays a role in regulating pH and is known to influence tumor growth and metastasis; its downregulation may promote a more acidic and hostile tumor microenvironment, facilitating tumor progression 30 . Similarly, ANKRD30A, SRARP, and PIP have all been implicated in breast cancer progression, with lower expression being associated with reduced differentiation and increased tumor aggressiveness 27 , 28 . And, PIP has been reported to be closely related to favorable outcomes in breast cancer, and its lower expression in BCY may further contribute to the poorer prognosis observed in this group 27 . These findings highlight the complex and context-dependent roles of gene expression in breast cancer prognosis, especially in BCY. Further research is needed to clarify the mechanisms by which these genes affect tumor behavior and their potential as therapeutic targets. In the BCY group, pathways related to cytokine-cytokine receptor interaction, Toll-like receptor signaling, and chemokine signaling were significantly enriched. These pathways are closely associated with inflammatory responses and immune modulation, suggesting that BCY may exhibit a more pro-inflammatory tumor microenvironment. This heightened inflammatory state could contribute to the increased tumor aggressiveness and poorer prognosis observed in BCY 31 , 32 . The GSEA results also highlighted the enrichment of pathways such as natural killer cell-mediated cytotoxicity, T cell receptor signaling, and antigen processing and presentation in BCY, indicating potential immune dysregulation that may affect the effectiveness of anti-tumor immune responses 33 . Moreover, pathways related to cell cycle, DNA replication, and p53 signaling were also enriched in BCY, indicating enhanced proliferative capacity and potential defects in genomic stability, which are consistent with the more aggressive tumor phenotype observed in BCY 34 – 36 . In contrast, the BCNY group showed significant enrichment in pathways related to metabolism and ECM interactions, such as tyrosine metabolism, ECM-receptor interaction, and focal adhesion. These pathways are known to be involved in tumor growth, metastasis, and cellular communication 37 – 39 . The enrichment of ECM-related pathways in BCNY may reflect a more stable tumor microenvironment, potentially contributing to the less aggressive nature of tumors in this age group. Moreover, the enrichment of metabolic pathways suggests that the tumors in BCNY may rely more on metabolic adaptations to sustain their growth, which could have implications for targeting metabolic vulnerabilities in these patients. The differential enrichment of these pathways underscores the importance of considering age-specific biological mechanisms when developing therapeutic strategies for breast cancer. For BCY, targeting inflammatory pathways and modulating the immune microenvironment could be potential therapeutic approaches to mitigate tumor aggressiveness. For example, inhibitors targeting cytokine-cytokine receptor interactions or Toll-like receptor signaling may help reduce inflammation and improve patient outcomes. Despite identifying significant differences in immune cell infiltration and gene expression between BCY and BCNY, this study has several limitations. First, the data were obtained from the METABRIC database, which, while providing rich genomic and clinical information, may have sample selection bias due to its retrospective nature, limiting generalizability. Second, immune cell abundance was inferred using the CIBERSORT algorithm, which relies on transcriptomic data and may not fully reflect the actual immune cell population. Third, this study did not explore dynamic changes in cell-cell interactions within the tumor microenvironment, which are critical to tumor progression. Future research should investigate immune-tumor interactions across age groups to better understand their roles in cancer development. Finally, one of the limitations of this study is the definition of age groups. The BCY group was defined as patients under 40 years of age, while BCNY included those aged 40 to less than 55 years. This age stratification may not fully capture the heterogeneity of breast cancer biology across different age ranges, and future studies should explore more granular age categorization to better understand age-specific tumor behaviors and responses to treatment. Declarations Ethics Statement Not applicable. Conflict of Interest Statement : The authors have no relevant financial or non-financial interests to disclose. Funding: This work was supported by Provincial-Level Clinical Key Specialty Construction in Qinghai Province. Author Contribution Z.Z. and Y.L. contributed to conceptualization, data curation, formal analysis, and investigation, with Y.L. and Y.T. leading the software development. C.G. led the writing of the main manuscript, and also contributed to formal analysis, supervision, and validation. X.L. participated in conceptualization, data curation, formal analysis, supervision, and validation. Z.Y. was responsible for data curation and visualization, while X.T. contributed to formal analysis, resource management, and supervision. Y.Y. conducted data curation, formal analysis, supervision, and visualization. X.B. was in charge of supervision and manuscript review and editing, and J.Z. participated in funding acquisition, supervision, and manuscript review and editing. All authors reviewed the manuscript Acknowledgments: Not applicable. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. References Bray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229–263. 10.3322/caac.21834 Lin CH, Chuang PY, Chiang CJ et al (2014) Distinct clinicopathological features and prognosis of emerging young-female breast cancer in an East Asian country: a nationwide cancer registry-based study. Oncologist 19(6):583–591. 10.1634/theoncologist.2014-0047 Zhong W, Tan L, Jiang WG et al (2019) Effect of younger age on survival outcomes in T1N0M0 breast cancer: A propensity score matching analysis. J Surg Oncol 119(8):1039–1046. 10.1002/jso.25457 Chinese Society of Clinical Oncology, Experts Committee on Breast Cancer, China Anti-Cancer Association (2023) the Society of Breast Cancer, Chinese Medical Association, Chinese Society of Breast Surgery. [Expert consensus on the diagnosis and treatment of young breast cancer in China (2022 Edition)]. Zhonghua Yi Xue Za Zhi 103(6):387–403. 10.3760/cma.j.cn112137-20220907-01895 Paluch-Shimon S, Cardoso F, Partridge AH et al (2022) ESO-ESMO fifth international consensus guidelines for breast cancer in young women (BCY5). Ann Oncol 33(11):1097–1118. 10.1016/j.annonc.2022.07.007 Franco I, Alshalalfa M, Hernandez A et al (2023) Genomic Characterization of Aggressive Breast Cancer in Younger Women. Ann Surg Oncol 30(12):7569–7578. 10.1245/s10434-023-14080-4 Ja J, Dt F (2015) T cell exclusion, immune privilege, and the tumor microenvironment. Sci (New York NY) 348(6230). 10.1126/science.aaa6204 Fridman WH, Pagès F, Sautès-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. 10.1038/nrc3245 Ew MB (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5). 10.1038/s41591-018-0014-x Medina A, Carballo J, González-Marcano E, Blanca I, Convit AF (2024) Breast cancer immunotherapy: Realities and advances. Cancer Innov 3(5):e140. 10.1002/cai2.140 Curtis C, Shah SP, Chin SF et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352. 10.1038/nature10983 Newman AM, Liu CL, Green MR et al (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453–457. 10.1038/nmeth.3337 Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA (2018) Profiling Tumor Infiltrating Immune Cells with CIBERSORT. Methods Mol Biol 1711:243–259. 10.1007/978-1-4939-7493-1_12 Ritchie ME, Phipson B, Wu D et al (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43(7):e47. 10.1093/nar/gkv007 Gómez-Flores-Ramos L, Castro-Sánchez A, Peña-Curiel O, Mohar-Betancourt A (2017) Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To DNA Mutations. Rev Invest Clin 69(4):181–192. 10.24875/ric.17002225 Yu Y, Jia X, Chen S et al (2024) Deciphering the role of apoptosis signature on the immune dynamics and therapeutic prognosis in breast cancer: Implication for immunotherapy. Front Genet 15:1332935. 10.3389/fgene.2024.1332935 Wang Z, Katsaros D, Wang J et al (2023) Machine learning-based cluster analysis of immune cell subtypes and breast cancer survival. Sci Rep 13(1):18962. 10.1038/s41598-023-45932-4 Ali HR, Chlon L, Pharoah PDP, Markowetz F, Caldas C (2016) Patterns of Immune Infiltration in Breast Cancer and Their Clinical Implications: A Gene-Expression-Based Retrospective Study. PLoS Med 13(12):e1002194. 10.1371/journal.pmed.1002194 J S, J S, A G, et al. Dendritic Cells Are Associated with Prognosis and Survival in Breast Cancer. Diagnostics (Basel Switzerland). (2021) ;11(4). 10.3390/diagnostics11040702 Matsumoto H, Thike AA, Li H et al (2016) Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer. Breast Cancer Res Treat 156(2):237–247. 10.1007/s10549-016-3743-x Li K, Tan G, Zhang X et al (2022) EIF4G1 Is a Potential Prognostic Biomarker of Breast Cancer. Biomolecules 12(12):1756. 10.3390/biom12121756 Schmidt M, Weyer-Elberich V, Hengstler JG et al (2018) Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population. Breast Cancer Res 20(1):15. 10.1186/s13058-018-0942-x Zhou Y, Tian Q, Gao H et al (2022) Correlation Between Immune-Related Genes and Tumor-Infiltrating Immune Cells With the Efficacy of Neoadjuvant Chemotherapy for Breast Cancer. Front Genet 13:905617. 10.3389/fgene.2022.905617 Xu Q, Chen S, Hu Y, Huang W (2021) Landscape of Immune Microenvironment Under Immune Cell Infiltration Pattern in Breast Cancer. Front Immunol 12:711433. 10.3389/fimmu.2021.711433 Mt M, Mp C (2022) Few, but Efficient: The Role of Mast Cells in Breast Cancer and Other Solid Tumors. Cancer Res 82(8). 10.1158/0008-5472.CAN-21-3424 Liu X, Wang M, Wang Q, Zhang H (2024) A ubiquitin-proteasome system-related signature to predict prognosis, immune infiltration, and therapy efficacy for breast cancer. Immunol Res 72(3):368–382. 10.1007/s12026-023-09440-x Sauer N, Matkowski I, Bodalska G, Murawski M, Dzięgiel P, Calik J (2023) Prognostic Role of Prolactin-Induced Protein (PIP) in Breast Cancer. Cells 12(18):2252. 10.3390/cells12182252 Golestan A, Tahmasebi A, Maghsoodi N, Faraji SN, Irajie C, Ramezani A (2024) Unveiling promising breast cancer biomarkers: an integrative approach combining bioinformatics analysis and experimental verification. BMC Cancer 24(1):155. 10.1186/s12885-024-11913-7 Sm C, Pj T, Ma D, Dw H (2022) Human Arylamine N-Acetyltransferase 1 (NAT1) Knockout in MDA-MB-231 Breast Cancer Cell Lines Leads to Transcription of NAT2. Front Pharmacol 12. 10.3389/fphar.2021.803254 Nj SL, Tv T (2023) Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer. Breast cancer research: BCR 25(1). 10.1186/s13058-023-01644-1 Yang H, Zhang Q, Xu M et al (2020) CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer 19(1):41. 10.1186/s12943-020-01165-x Pallathadka H, Khaleel AQ, Zwamel AH et al (2024) Multi-Drug Resistance and Breast Cancer Progression via Toll-Like Receptors (TLRs) Signaling. Cell Biochem Biophys . Published online August 7. 10.1007/s12013-024-01418-2 Wu X, Li T, Jiang R, Yang X, Guo H, Yang R (2023) Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects. Mol Cancer 22(1):194. 10.1186/s12943-023-01899-4 Li S, Wang L, Wang Y, Zhang C, Hong Z, Han Z (2022) The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment. J Hematol Oncol 15(1):147. 10.1186/s13045-022-01360-x Khamidullina AI, Abramenko YE, Bruter AV, Tatarskiy VV (2024) Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets. Int J Mol Sci 25(2):1263. 10.3390/ijms25021263 Marei HE, Althani A, Afifi N et al (2021) p53 signaling in cancer progression and therapy. Cancer Cell Int 21(1):703. 10.1186/s12935-021-02396-8 X T, Y Y (2023) Focal adhesion kinase: from biological functions to therapeutic strategies. Experimental Hematol Oncol 12(1). 10.1186/s40164-023-00446-7 Nazemi M, Yanes B, Martinez ML et al (2024) The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. PLoS Biol 22(1):e3002406. 10.1371/journal.pbio.3002406 Z Y (2023) Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol Cancer 22(1). 10.1186/s12943-023-01744-8 Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.pdf Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-5382194","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":375380694,"identity":"d12297b3-28a5-41f4-9039-3374e20d4810","order_by":0,"name":"Zijun Zhu","email":"","orcid":"","institution":"Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University","correspondingAuthor":false,"prefix":"","firstName":"Zijun","middleName":"","lastName":"Zhu","suffix":""},{"id":375380695,"identity":"3ff2c29d-3c06-4e8b-ab35-9a359b2244e6","order_by":1,"name":"Chen Gao","email":"","orcid":"","institution":"GanSu Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Gao","suffix":""},{"id":375380696,"identity":"e7ea14ad-2ba3-4400-8743-ceed68d4fe19","order_by":2,"name":"Yongxin Li","email":"","orcid":"","institution":"Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University","correspondingAuthor":false,"prefix":"","firstName":"Yongxin","middleName":"","lastName":"Li","suffix":""},{"id":375380697,"identity":"b4c7215a-d86e-4150-b649-546820702596","order_by":3,"name":"Xiao Liang","email":"","orcid":"","institution":"Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Liang","suffix":""},{"id":375380698,"identity":"0826418a-c942-4e67-8acc-2c2838bd3428","order_by":4,"name":"Zhancai Ye","email":"","orcid":"","institution":"The Second People’s Hospital of Gomlud City","correspondingAuthor":false,"prefix":"","firstName":"Zhancai","middleName":"","lastName":"Ye","suffix":""},{"id":375380699,"identity":"58b76316-6e14-419b-94cf-b74a198aa444","order_by":5,"name":"Xinlong Tao","email":"","orcid":"","institution":"Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University","correspondingAuthor":false,"prefix":"","firstName":"Xinlong","middleName":"","lastName":"Tao","suffix":""},{"id":375380700,"identity":"e2d99c65-94c4-4f8b-9bf9-af2b1a8bc2de","order_by":6,"name":"Yinyin Ye","email":"","orcid":"","institution":"Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University","correspondingAuthor":false,"prefix":"","firstName":"Yinyin","middleName":"","lastName":"Ye","suffix":""},{"id":375380705,"identity":"c919c65c-d718-4be5-8ab6-16635508a872","order_by":7,"name":"Yaming Tian","email":"","orcid":"","institution":"Qinghai University","correspondingAuthor":false,"prefix":"","firstName":"Yaming","middleName":"","lastName":"Tian","suffix":""},{"id":375380706,"identity":"82bb8e5a-d844-478a-adab-18ea220e0f5b","order_by":8,"name":"Xiaorong Bai","email":"","orcid":"","institution":"GanSu Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaorong","middleName":"","lastName":"Bai","suffix":""},{"id":375380707,"identity":"5570a625-1aa1-4d97-a443-62ebe3f399a4","order_by":9,"name":"Jiuda Zhao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACxmYGBgkGhgMMDOyNjQ8+kKaF53Cz4QxibYJokUhvk+YgRjlzO4/hjR9/7sjzSz5skGZgsJPTbSDoMB5jyx6eZ4YzZyc2GBcwJBubHSCsxUyCR+Iw44bbiQ3JMxgOJG4jRovkH4PD9htuHmw4zEOsFmmehMOJG24wNjYTqYWt2FrmwOHkmT2JzYwzDIjwi2H/4Y033/w5bNvPfvz5jw8VdnKEtTSgcA0IKAcBeSLUjIJRMApGwUgHACLyRPwEd1EhAAAAAElFTkSuQmCC","orcid":"","institution":"Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University","correspondingAuthor":true,"prefix":"","firstName":"Jiuda","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2024-11-03 13:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5382194/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5382194/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70379607,"identity":"4a4b935f-17aa-4e0e-93a4-d6d27242f0d5","added_by":"auto","created_at":"2024-12-02 15:49:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":68159,"visible":true,"origin":"","legend":"\u003cp\u003ePopulation included in the study.\u003c/p\u003e\n\u003cp\u003eMETABRIC: Molecular Taxonomy of Breast Cancer International Consortium.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5382194/v1/4f1e848919b5163fef6cd189.png"},{"id":70379611,"identity":"35cef5b1-e8b8-4c89-89f1-6364edd0dc84","added_by":"auto","created_at":"2024-12-02 15:49:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":135886,"visible":true,"origin":"","legend":"\u003cp\u003eViolin plot showed the ratio differentiation of 22 kinds of immune cells between breast cancer with young and non-young patients, and Wilcoxon rank sum was used for the significance test.\u003c/p\u003e\n\u003cp\u003eBCY, breast cancer with young patients. BCNY, breast cancer with non-young patients.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5382194/v1/33c350dfcba814a9002616c7.png"},{"id":70379609,"identity":"8416a54f-1807-4bcb-8620-3e1f0950ad1d","added_by":"auto","created_at":"2024-12-02 15:49:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":121385,"visible":true,"origin":"","legend":"\u003cp\u003eGene set enrichment analysis in breast cancer with young breast.\u003c/p\u003e\n\u003cp\u003eNES, Normalized Enrichment Score\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5382194/v1/abf0cc117d96d31424914ae3.png"},{"id":70379608,"identity":"6b971fcb-fcda-4758-b289-bbdd3bc05ea3","added_by":"auto","created_at":"2024-12-02 15:49:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":60865,"visible":true,"origin":"","legend":"\u003cp\u003eGene set enrichment analysis in breast cancer with non-young breast.\u003c/p\u003e\n\u003cp\u003eNES, Normalized Enrichment Score\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5382194/v1/4c7777ba3975b4d7cccfd5fa.png"},{"id":70875751,"identity":"61d9ff00-adaa-4a31-9a99-d58ccea8f5ce","added_by":"auto","created_at":"2024-12-08 18:46:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":732189,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5382194/v1/28e83c87-7bf2-4599-872c-ca209c03ad4d.pdf"},{"id":70379610,"identity":"a34c08e9-47c0-4d54-a514-23ef0e02401f","added_by":"auto","created_at":"2024-12-02 15:49:53","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":5951896,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5382194/v1/abde234aadeba64a2ebcf559.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Distinct Immune Landscape and Gene Expression Profiles in Breast Cancer: Young vs. Non-Young Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer remains one of the most prevalent malignancies affecting women globally.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e According to recent data, it accounts for 11.6% of all new cancer diagnoses, making it the second most common cancer type worldwide.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Despite advances in treatment that have led to improvements in overall survival rates, breast cancer still contributes significantly to cancer-related mortality, responsible for 6.9% of all cancer deaths.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e This high incidence emphasizes the need for further research in breast cancer.\u003c/p\u003e \u003cp\u003eSignificant differences in clinical characteristics and prognosis have been observed across different age groups of breast cancer patients.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Breast cancer with young patients (BCY), defined by clinical guidelines as those under 40 years of age,\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e often present with more aggressive clinical features and poorer prognoses.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn recent years, many studies have elucidated the reasons for poor outcomes in BCY, focusing primarily on clinicopathological, molecular, and genomic differences between BCY and breast cancer with non-young patients (BCNY), providing valuable insights into the unique biological behavior of breast cancer in BCY.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e However, despite these advances, the role of the tumor microenvironment particularly tumour-infiltrating immune cells (TIICs) different age groups remains underexplored. TIICs plays a pivotal role in tumor progression, metastasis, and response to therapy. \u003csup\u003e\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Differences in the composition and functional states of these immune cells, as well as underlying gene expression profiles, may be critical factors contributing to the more aggressive nature and poorer prognosis of BCY. Nonetheless, research specifically comparing TIICs and gene expression between different age groups is notably absent.\u003c/p\u003e \u003cp\u003eThis study, therefore, aims to investigate the differences in immune cell infiltration and gene expression between BCY and BCNY, and to elucidate the implications of these differences for patient prognosis. By examining both immune cell infiltration across various molecular subtypes, we seek to identify key immunological characteristics that influence the prognosis of BCY, ultimately providing a theoretical foundation for the development of personalized therapeutic strategies.\u003c/p\u003e "},{"header":"Methods","content":"\u003col\u003e\n \u003cli\u003e\u003cstrong\u003eData Source\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe data for this study were sourced from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database, which is a comprehensive repository of genomic and clinical data on breast cancer patients.\u003csup\u003e11\u003c/sup\u003e The METABRIC database includes extensive information on patient demographics, tumor characteristics, treatment outcomes, and high-throughput molecular data, such as gene expression profiles. This study complies with the requirements for using the METABRIC databases, therefore no ethical committee approval was needed.\u0026nbsp;\u003c/p\u003e\n\u003col start=\"2\"\u003e\n \u003cli\u003e\u003cstrong\u003ePatient Selection\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eTo achieve the study\u0026apos;s objective of comparing tumor-infiltrating immune cells (TIICs) between BCY and BCNY, we applied specific inclusion and exclusion criteria to select the appropriate patient cohorts. The inclusion criteria were: (1) patients diagnosed with primary breast cancer; (2) availability of detailed diagnostic age; (3) availability of transcriptomic sequencing data, allowing for comprehensive analysis of gene expression profiles and immune cell infiltration. The exclusion criteria were: (1) patients diagnosed at or above the age of 55 years, as these patients are outside the study\u0026apos;s focus age groups; (2) patients without information on PAM50 subtypes or Claudin-low subtype, as this data is necessary for subgroup analysis. The final cohort was divided into two groups based on age: the BCY group (patients under 40 years of age) and the BCNY group (patients aged 40 to less than 55 years). This age-based stratification was guided by both clinical guidelines\u003csup\u003e4,5\u003c/sup\u003e.\u003c/p\u003e\n\u003col start=\"3\"\u003e\n \u003cli\u003e\u003cstrong\u003eTIICs analysis\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eTo estimate the relative abundance of 22 TIICs types in breast cancer specimens, we employed the cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm.\u003csup\u003e12\u003c/sup\u003e This computational tool is specifically designed to deconvolute complex gene expression data, allowing for the identification and quantification of immune cell populations within heterogeneous tissue samples. By leveraging normalized gene expression data, CIBERSORT provides a detailed profile of TIICs in each sample.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this analysis, we utilized the LM22 signature matrix, which includes 547 genes that serve as markers for 22 distinct immune cell types,\u003csup\u003e13\u003c/sup\u003e such as B cells, T cells, natural killer cells, macrophages, dendritic cells, eosinophils, and neutrophils. CIBERSORT applies Monte Carlo sampling to estimate p-values, which assess the confidence of the deconvolution results for each sample. In this study, only samples with a \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05 were included in the final analysis to ensure the robustness and accuracy of the inferred immune cell proportions.\u003csup\u003e12\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003col start=\"4\"\u003e\n \u003cli\u003e\u003cstrong\u003eDifferentially expressed genes (DEGs) and gene set enrichment analysis (GSEA)\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eDEGs analysis was conducted using the \u0026quot;limma\u0026quot; package in R, which applies a linear model to assess expression differences.\u003csup\u003e14\u003c/sup\u003e Genes with an adjusted p-value \u0026lt; 0.05 and an absolute log fold change (|logFC|) \u0026gt; 1 were considered significantly differentially expressed. Following this, GSEA was performed to identify biological pathways and processes enriched in the BCY versus BCNY groups.\u003c/p\u003e\n\u003col start=\"5\"\u003e\n \u003cli\u003e\u003cstrong\u003eKaplan-Meier (KM) curve generation based on DEGs\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eTo further explore the prognostic significance of DEGs, KM survival curves were generated using data from all breast cancer patients in the METABRIC database. Patients were stratified into high and low expression groups based on the median expression level of each differentially expressed gene. The log-rank test was used to compare survival outcomes between these groups, providing insights into the potential impact of these DEGs on relapse free survival (RFS).\u003c/p\u003e\n\u003col start=\"6\"\u003e\n \u003cli\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eStatistical comparisons between groups were performed using Welch\u0026apos;s two-sample t-test and Pearson\u0026rsquo;s chi-squared test, depending on the distribution of the data. For the TIICs data, the Wilcoxon rank-sum test was applied to assess the statistical significance of differences between the BCY and BCNY groups. To execute the CIBERSORT algorithm, the following essential R packages were required: \u0026quot;e1071\u0026quot;, \u0026quot;parallel\u0026quot;, and \u0026quot;preprocessCore\u0026quot;. The LM22 signature matrix file (\u0026quot;LM22.txt\u0026quot;) was obtained from the CIBERSORT website. Kaplan-Meier (KM) survival curves were generated using the \u0026quot;survival\u0026quot; package in R. All statistical analyses were conducted using R software (version 4.3.3), and \u003cem\u003ep\u003c/em\u003e-values \u0026lt; 0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e1. Patient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included 640 patients with breast cancer: 120 in the BCY group and 520 in the BCNY group. A data screening flow chart is provided in Figure 1, with detailed characteristics shown in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" style=\"width: 589px;\" width=\"589\" height=\"890\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe BCY group had a higher proportion of patients diagnosed with invasive ductal carcinoma (IDC) at 92.5%, compared to 79.2% in the BCNY group. The BCY group had a higher prevalence of basal and claudin-low subtypes, with 29.2% and 18.3% of patients respectively, compared to 12.7% and 6.5% in the BCNY group. In contrast, the BCNY group had more luminal A and luminal B subtypes, with luminal A present in 42.3% of patients and luminal B in 25.8%, compared to 18.3% and 10.0% in the BCY group (p \u0026lt; 0.001). The BCY group also had a significantly higher proportion of grade 3 tumors (78.3% vs. 49.4%, p \u0026lt; 0.001), reflecting a more aggressive disease profile. The BCY group also had a significantly higher proportion of grade 3 tumors (78.3% vs. 49.4%, p \u0026lt; 0.001), reflecting a more aggressive disease profile. Hormone receptor negativity was more prevalent in the BCY group, with 62.5% of patients being estrogen receptor (ER) negative and 67.5% being progesterone receptor (PR) negative, compared to 36.2% and 42.5% in the BCNY group (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). Although the BCY group had a higher rate of human epidermal growth factor receptor 2 (HER2) positivity, this difference was not statistically significant (\u003cem\u003ep\u003c/em\u003e = 0.059). Chemotherapy was more frequently used in the BCY group (64.2% vs. 38.1, p \u0026lt; 0.001), whereas hormone therapy was more common in the BCNY group. Radiotherapy usage did not differ significantly between the groups (p = 0.300).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. TIICs analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall analysis of TIICs showed that the BCY group had lower infiltration levels of CD4 memory T cells, gamma delta T cells, resting NK cells, M2 macrophages, resting mast cells, and neutrophils when compared to the BCNY group (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05). In contrast, the BCY group showed higher proportions of M0 macrophages and activated dendritic cells in Figure 2.\u003c/p\u003e\n\u003cp\u003eSupplementary figures 1-6 further revealed the differences in TIICs in different subtypes of breast cancer between young and non-young patients. In the luminal A subtype, the BCY group demonstrated reduced infiltration of M2 macrophages and increased infiltration of activated dendritic cells. For the luminal B subtype, the BCY group exhibited lower levels of CD8 T cells, follicular helper T cells, and M1 macrophages, while showing higher levels of M2 macrophages. In the Her2-enriched subtype, the BCY group had decreased infiltration of gamma delta T cells but increased infiltration of activated dendritic cells. In the basal subtype, the BCY group exhibited reduced infiltration of M2 macrophages, with a higher prevalence of activated dendritic cells. The the normal subtype showed that the BCY group had lower levels of CD4 memory T cells and resting NK cells, accompanied by increased infiltration of monocytes. Lastly, in the claudin-low subtype, the BCY group demonstrated higher levels of regulatory T cells and activated dendritic cells.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. DGEs analysis and survival analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 11 genes that were significantly differentially expressed between the two groups. FDCSP and GABRP were upregulated in the BCY group, while the following genes were upregulated in the BCNY group: FOXA1, ESR1, MLPH, NAT1, CA12, ANKRD30A, SRARP, TFF3, and PIP. The heatmap (Supplementary figure 7) and volcano plot (Supplementary figure 8) further illustrate these differences. In supplementary figure 9 that KM survival curves indicated that high expression of the genes FDCSP, NAT1, CA12, ANKRD30A, SRARP, ESR1 and PIP was significantly associated with greater RFS.\u0026nbsp;FOXA1, GABRP, MLPH, and TFF3 did not show a statistically significant association with RFS in breast cancer, as shown in Supplementary figure 10.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. Gene set enrichment analysis in BCY and BCNY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 3 showed that pathways such as cytokine cytokine receptor interaction, chemokine signaling pathway, natural killer cell mediated cytotoxicity, T cell receptor signaling pathway, toll like receptor signaling pathway, systemic lupus erythematosus, pyrimidine metabolism, progesterone mediated oocyte maturation, antigen processing and presentation, oocyte meiosis, nod like receptor signaling pathway, p53 signaling pathway, allograft rejection, graft versus host disease, primary immunodeficiency, cell cycle, proteasome, and DNA replication were significantly enriched in BCY group (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05). In BCNY group, pathways such as tyrosine metabolism, drug metabolism cytochrome P450, EMC receptor interaction, hypertrophic cardiomyopathy, TGF beta signaling pathway, and focal adhesion were significantly enriched (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05), as shown in Figure 4.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study revealed significant differences in immune cell infiltration and gene expression between BCY and BCNY. BCY patients had higher levels of M0 macrophages and activated dendritic cells, while M2 macrophages, CD4 memory T cells, and neutrophils were lower compared to BCNY patients. Immune infiltration patterns also varied across molecular subtypes within BCY. Differential gene expression analysis showed that FDCSP and GABRP were upregulated in BCY, whereas FOXA1, ESR1, and other genes were upregulated in BCNY. GSEA indicated that inflammation and immune-related pathways were enriched in BCY, while metabolism and ECM-related pathways were prominent in BCNY.\u003c/p\u003e \u003cp\u003eThe findings of this study align with, yet also diverge from, previous literature exploring the molecular characteristics of BCY. Existing research indicates that BCY often exhibit unique genomic signatures, higher frequencies of aggressive subtypes, and distinct gene expression patterns compared to BCNY. For instance, studies by G\u0026oacute;mez-Flores-Ramos et al. have showed that BCY often present with lower mRNA expression of estrogen receptors and higher expression of proliferation markers such as HER2 and Ki67. Our study, however, highlighted significant differences in immune cell infiltration and gene expression profiles, emphasizing an immunological perspective that has not been extensively covered in these earlier genomic-focused analyses\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The enrichment of specific immune pathways and the differential expression of immune-related genes suggest that the immune landscape could be a key factor contributing to the poor prognosis observed in BCY. This distinct focus complements the genomic insights provided by other researchers and supports the need for a more integrated understanding of both the genetic and immune components of BCY.\u003c/p\u003e \u003cp\u003eThe observed differences in immune cell infiltration between BCY and BCNY have important clinical implications. The increased proportion of M0 macrophages and activated dendritic cells in BCY may contribute to the more aggressive tumor phenotype often observed in BCY. Several studies have reported an association between higher levels of M0 macrophages and poorer prognosis in breast cancer, suggesting that the higher prevalence of M0 macrophages in BCY may be a significant factor driving their aggressive disease course\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. M0 macrophages are often considered a precursor state that can be influenced by the tumor microenvironment to promote tumor growth and metastasis, and their elevated levels in BCY may reflect a greater potential for tumor-promoting immune modulation. Furthermore, recent research has also linked higher levels of activated dendritic cells with poorer prognosis in triple-negative breast cancer\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. This suggests that the increased presence of activated dendritic cells in BCY, particularly those with triple-negative subtypes, may contribute to a more aggressive tumor phenotype and reduced survival outcomes. Additionally, the lower levels of CD4 memory T cells and neutrophils in BCY could indicate impaired adaptive immune responses and decreased recruitment of innate immune cells, respectively, both of which may contribute to the poorer prognosis observed in this group. Several studies have reported that lower levels of CD4 memory T cells and neutrophils are associated with worse prognosis in breast cancer\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, suggesting that their reduced presence in BCY may exacerbate disease progression and lead to unfavorable outcomes. Moreover, studies have shown that lower levels of resting mast cells are associated with poorer prognosis in breast cancer patients\u003csup\u003e\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The reduced presence of resting mast cells in BCY might, therefore, be another contributing factor to the poorer prognosis in this group, as these cells play a role in modulating immune responses within the tumor microenvironment. These findings highlight the need for age-specific approaches to immunotherapy that take into account the unique immune landscape of BCY patients. Developing therapies that specifically address the distinct immunological features of young breast cancer patients may help improve survival outcomes.\u003c/p\u003e \u003cp\u003eThe differential gene expression observed between BCY and BCNY provides important insights into the biological underpinnings of the distinct tumor behaviors seen in these age groups. In the BCY group, the upregulation of FDCSP and GABRP genes suggests potential roles in tumor progression; however, our findings indicate a nuanced prognostic impact for these genes. FDCSP was found to be associated with better prognosis in our cohort \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, despite other studies linking its upregulation with poor outcomes in breast cancer. This discrepancy may be due to differences in tumor subtype distributions, underlying genetic backgrounds, or variations in the tumor microenvironment. The exact role of FDCSP in breast cancer remains to be fully elucidated, but our results suggest it may have context-dependent functions, potentially playing a protective role under certain conditions by influencing immune cell interactions or inhibiting tumor-promoting pathways. On the other hand, GABRP has been previously reported to be associated with poor prognosis in breast cancer, did not show significant prognostic impact in our analysis when comparing high and low expression groups. It is also possible that the influence of GABRP on prognosis is subtype-specific, and further research focusing on different breast cancer subtypes may be needed to clarify its role. We found that the genes NAT1, CA12, ANKRD30A, SRARP, and PIP were downregulated in BCY compared to BCNY, and their lower expression was associated with poorer RFS. This finding is consistent with other studies reporting that lower expression of these genes is linked to worse prognosis in breast cancer\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. NAT1, an enzyme involved in acetylation, has been associated with DNA repair and cellular homeostasis, and its reduced expression may compromise these processes, leading to a more aggressive tumor phenotype\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. CA12, a carbonic anhydrase, plays a role in regulating pH and is known to influence tumor growth and metastasis; its downregulation may promote a more acidic and hostile tumor microenvironment, facilitating tumor progression\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Similarly, ANKRD30A, SRARP, and PIP have all been implicated in breast cancer progression, with lower expression being associated with reduced differentiation and increased tumor aggressiveness\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. And, PIP has been reported to be closely related to favorable outcomes in breast cancer, and its lower expression in BCY may further contribute to the poorer prognosis observed in this group\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. These findings highlight the complex and context-dependent roles of gene expression in breast cancer prognosis, especially in BCY. Further research is needed to clarify the mechanisms by which these genes affect tumor behavior and their potential as therapeutic targets.\u003c/p\u003e \u003cp\u003eIn the BCY group, pathways related to cytokine-cytokine receptor interaction, Toll-like receptor signaling, and chemokine signaling were significantly enriched. These pathways are closely associated with inflammatory responses and immune modulation, suggesting that BCY may exhibit a more pro-inflammatory tumor microenvironment. This heightened inflammatory state could contribute to the increased tumor aggressiveness and poorer prognosis observed in BCY\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The GSEA results also highlighted the enrichment of pathways such as natural killer cell-mediated cytotoxicity, T cell receptor signaling, and antigen processing and presentation in BCY, indicating potential immune dysregulation that may affect the effectiveness of anti-tumor immune responses\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Moreover, pathways related to cell cycle, DNA replication, and p53 signaling were also enriched in BCY, indicating enhanced proliferative capacity and potential defects in genomic stability, which are consistent with the more aggressive tumor phenotype observed in BCY\u003csup\u003e\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. In contrast, the BCNY group showed significant enrichment in pathways related to metabolism and ECM interactions, such as tyrosine metabolism, ECM-receptor interaction, and focal adhesion. These pathways are known to be involved in tumor growth, metastasis, and cellular communication\u003csup\u003e\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. The enrichment of ECM-related pathways in BCNY may reflect a more stable tumor microenvironment, potentially contributing to the less aggressive nature of tumors in this age group. Moreover, the enrichment of metabolic pathways suggests that the tumors in BCNY may rely more on metabolic adaptations to sustain their growth, which could have implications for targeting metabolic vulnerabilities in these patients. The differential enrichment of these pathways underscores the importance of considering age-specific biological mechanisms when developing therapeutic strategies for breast cancer. For BCY, targeting inflammatory pathways and modulating the immune microenvironment could be potential therapeutic approaches to mitigate tumor aggressiveness. For example, inhibitors targeting cytokine-cytokine receptor interactions or Toll-like receptor signaling may help reduce inflammation and improve patient outcomes.\u003c/p\u003e \u003cp\u003eDespite identifying significant differences in immune cell infiltration and gene expression between BCY and BCNY, this study has several limitations. First, the data were obtained from the METABRIC database, which, while providing rich genomic and clinical information, may have sample selection bias due to its retrospective nature, limiting generalizability. Second, immune cell abundance was inferred using the CIBERSORT algorithm, which relies on transcriptomic data and may not fully reflect the actual immune cell population. Third, this study did not explore dynamic changes in cell-cell interactions within the tumor microenvironment, which are critical to tumor progression. Future research should investigate immune-tumor interactions across age groups to better understand their roles in cancer development. Finally, one of the limitations of this study is the definition of age groups. The BCY group was defined as patients under 40 years of age, while BCNY included those aged 40 to less than 55 years. This age stratification may not fully capture the heterogeneity of breast cancer biology across different age ranges, and future studies should explore more granular age categorization to better understand age-specific tumor behaviors and responses to treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics Statement\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e:\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eThis work was supported by Provincial-Level Clinical Key Specialty Construction in Qinghai Province.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eZ.Z. and Y.L. contributed to conceptualization, data curation, formal analysis, and investigation, with Y.L. and Y.T. leading the software development. C.G. led the writing of the main manuscript, and also contributed to formal analysis, supervision, and validation. X.L. participated in conceptualization, data curation, formal analysis, supervision, and validation. Z.Y. was responsible for data curation and visualization, while X.T. contributed to formal analysis, resource management, and supervision. Y.Y. conducted data curation, formal analysis, supervision, and visualization. X.B. was in charge of supervision and manuscript review and editing, and J.Z. participated in funding acquisition, supervision, and manuscript review and editing. All authors reviewed the manuscript\u003c/p\u003e\n\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eData availability statement:\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229\u0026ndash;263. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3322/caac.21834\u003c/span\u003e\u003cspan address=\"10.3322/caac.21834\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin CH, Chuang PY, Chiang CJ et al (2014) Distinct clinicopathological features and prognosis of emerging young-female breast cancer in an East Asian country: a nationwide cancer registry-based study. Oncologist 19(6):583\u0026ndash;591. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1634/theoncologist.2014-0047\u003c/span\u003e\u003cspan address=\"10.1634/theoncologist.2014-0047\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhong W, Tan L, Jiang WG et al (2019) Effect of younger age on survival outcomes in T1N0M0 breast cancer: A propensity score matching analysis. J Surg Oncol 119(8):1039\u0026ndash;1046. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jso.25457\u003c/span\u003e\u003cspan address=\"10.1002/jso.25457\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChinese Society of Clinical Oncology, Experts Committee on Breast Cancer, China Anti-Cancer Association (2023) the Society of Breast Cancer, Chinese Medical Association, Chinese Society of Breast Surgery. [Expert consensus on the diagnosis and treatment of young breast cancer in China (2022 Edition)]. Zhonghua Yi Xue Za Zhi 103(6):387\u0026ndash;403. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3760/cma.j.cn112137-20220907-01895\u003c/span\u003e\u003cspan address=\"10.3760/cma.j.cn112137-20220907-01895\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaluch-Shimon S, Cardoso F, Partridge AH et al (2022) ESO-ESMO fifth international consensus guidelines for breast cancer in young women (BCY5). Ann Oncol 33(11):1097\u0026ndash;1118. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.annonc.2022.07.007\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2022.07.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranco I, Alshalalfa M, Hernandez A et al (2023) Genomic Characterization of Aggressive Breast Cancer in Younger Women. Ann Surg Oncol 30(12):7569\u0026ndash;7578. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1245/s10434-023-14080-4\u003c/span\u003e\u003cspan address=\"10.1245/s10434-023-14080-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJa J, Dt F (2015) T cell exclusion, immune privilege, and the tumor microenvironment. Sci (New York NY) 348(6230). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.aaa6204\u003c/span\u003e\u003cspan address=\"10.1126/science.aaa6204\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFridman WH, Pag\u0026egrave;s F, Saut\u0026egrave;s-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298\u0026ndash;306. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nrc3245\u003c/span\u003e\u003cspan address=\"10.1038/nrc3245\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEw MB (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41591-018-0014-x\u003c/span\u003e\u003cspan address=\"10.1038/s41591-018-0014-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMedina A, Carballo J, Gonz\u0026aacute;lez-Marcano E, Blanca I, Convit AF (2024) Breast cancer immunotherapy: Realities and advances. Cancer Innov 3(5):e140. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cai2.140\u003c/span\u003e\u003cspan address=\"10.1002/cai2.140\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCurtis C, Shah SP, Chin SF et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346\u0026ndash;352. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nature10983\u003c/span\u003e\u003cspan address=\"10.1038/nature10983\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNewman AM, Liu CL, Green MR et al (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453\u0026ndash;457. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nmeth.3337\u003c/span\u003e\u003cspan address=\"10.1038/nmeth.3337\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA (2018) Profiling Tumor Infiltrating Immune Cells with CIBERSORT. Methods Mol Biol 1711:243\u0026ndash;259. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/978-1-4939-7493-1_12\u003c/span\u003e\u003cspan address=\"10.1007/978-1-4939-7493-1_12\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRitchie ME, Phipson B, Wu D et al (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43(7):e47. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/nar/gkv007\u003c/span\u003e\u003cspan address=\"10.1093/nar/gkv007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eG\u0026oacute;mez-Flores-Ramos L, Castro-S\u0026aacute;nchez A, Pe\u0026ntilde;a-Curiel O, Mohar-Betancourt A (2017) Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To DNA Mutations. Rev Invest Clin 69(4):181\u0026ndash;192. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.24875/ric.17002225\u003c/span\u003e\u003cspan address=\"10.24875/ric.17002225\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu Y, Jia X, Chen S et al (2024) Deciphering the role of apoptosis signature on the immune dynamics and therapeutic prognosis in breast cancer: Implication for immunotherapy. Front Genet 15:1332935. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fgene.2024.1332935\u003c/span\u003e\u003cspan address=\"10.3389/fgene.2024.1332935\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Katsaros D, Wang J et al (2023) Machine learning-based cluster analysis of immune cell subtypes and breast cancer survival. Sci Rep 13(1):18962. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-023-45932-4\u003c/span\u003e\u003cspan address=\"10.1038/s41598-023-45932-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAli HR, Chlon L, Pharoah PDP, Markowetz F, Caldas C (2016) Patterns of Immune Infiltration in Breast Cancer and Their Clinical Implications: A Gene-Expression-Based Retrospective Study. PLoS Med 13(12):e1002194. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pmed.1002194\u003c/span\u003e\u003cspan address=\"10.1371/journal.pmed.1002194\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ S, J S, A G, et al. Dendritic Cells Are Associated with Prognosis and Survival in Breast Cancer. Diagnostics (Basel Switzerland). (2021) ;11(4). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/diagnostics11040702\u003c/span\u003e\u003cspan address=\"10.3390/diagnostics11040702\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsumoto H, Thike AA, Li H et al (2016) Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer. Breast Cancer Res Treat 156(2):237\u0026ndash;247. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10549-016-3743-x\u003c/span\u003e\u003cspan address=\"10.1007/s10549-016-3743-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi K, Tan G, Zhang X et al (2022) EIF4G1 Is a Potential Prognostic Biomarker of Breast Cancer. Biomolecules 12(12):1756. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/biom12121756\u003c/span\u003e\u003cspan address=\"10.3390/biom12121756\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmidt M, Weyer-Elberich V, Hengstler JG et al (2018) Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population. Breast Cancer Res 20(1):15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13058-018-0942-x\u003c/span\u003e\u003cspan address=\"10.1186/s13058-018-0942-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou Y, Tian Q, Gao H et al (2022) Correlation Between Immune-Related Genes and Tumor-Infiltrating Immune Cells With the Efficacy of Neoadjuvant Chemotherapy for Breast Cancer. Front Genet 13:905617. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fgene.2022.905617\u003c/span\u003e\u003cspan address=\"10.3389/fgene.2022.905617\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu Q, Chen S, Hu Y, Huang W (2021) Landscape of Immune Microenvironment Under Immune Cell Infiltration Pattern in Breast Cancer. Front Immunol 12:711433. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fimmu.2021.711433\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2021.711433\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMt M, Mp C (2022) Few, but Efficient: The Role of Mast Cells in Breast Cancer and Other Solid Tumors. Cancer Res 82(8). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/0008-5472.CAN-21-3424\u003c/span\u003e\u003cspan address=\"10.1158/0008-5472.CAN-21-3424\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu X, Wang M, Wang Q, Zhang H (2024) A ubiquitin-proteasome system-related signature to predict prognosis, immune infiltration, and therapy efficacy for breast cancer. Immunol Res 72(3):368\u0026ndash;382. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12026-023-09440-x\u003c/span\u003e\u003cspan address=\"10.1007/s12026-023-09440-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSauer N, Matkowski I, Bodalska G, Murawski M, Dzięgiel P, Calik J (2023) Prognostic Role of Prolactin-Induced Protein (PIP) in Breast Cancer. Cells 12(18):2252. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cells12182252\u003c/span\u003e\u003cspan address=\"10.3390/cells12182252\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGolestan A, Tahmasebi A, Maghsoodi N, Faraji SN, Irajie C, Ramezani A (2024) Unveiling promising breast cancer biomarkers: an integrative approach combining bioinformatics analysis and experimental verification. BMC Cancer 24(1):155. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12885-024-11913-7\u003c/span\u003e\u003cspan address=\"10.1186/s12885-024-11913-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSm C, Pj T, Ma D, Dw H (2022) Human Arylamine N-Acetyltransferase 1 (NAT1) Knockout in MDA-MB-231 Breast Cancer Cell Lines Leads to Transcription of NAT2. Front Pharmacol 12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fphar.2021.803254\u003c/span\u003e\u003cspan address=\"10.3389/fphar.2021.803254\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNj SL, Tv T (2023) Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer. Breast cancer research: BCR 25(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13058-023-01644-1\u003c/span\u003e\u003cspan address=\"10.1186/s13058-023-01644-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang H, Zhang Q, Xu M et al (2020) CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer 19(1):41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12943-020-01165-x\u003c/span\u003e\u003cspan address=\"10.1186/s12943-020-01165-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePallathadka H, Khaleel AQ, Zwamel AH et al (2024) Multi-Drug Resistance and Breast Cancer Progression via Toll-Like Receptors (TLRs) Signaling. \u003cem\u003eCell Biochem Biophys\u003c/em\u003e. Published online August 7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12013-024-01418-2\u003c/span\u003e\u003cspan address=\"10.1007/s12013-024-01418-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu X, Li T, Jiang R, Yang X, Guo H, Yang R (2023) Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects. Mol Cancer 22(1):194. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12943-023-01899-4\u003c/span\u003e\u003cspan address=\"10.1186/s12943-023-01899-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi S, Wang L, Wang Y, Zhang C, Hong Z, Han Z (2022) The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment. J Hematol Oncol 15(1):147. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13045-022-01360-x\u003c/span\u003e\u003cspan address=\"10.1186/s13045-022-01360-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhamidullina AI, Abramenko YE, Bruter AV, Tatarskiy VV (2024) Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets. Int J Mol Sci 25(2):1263. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ijms25021263\u003c/span\u003e\u003cspan address=\"10.3390/ijms25021263\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarei HE, Althani A, Afifi N et al (2021) p53 signaling in cancer progression and therapy. Cancer Cell Int 21(1):703. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12935-021-02396-8\u003c/span\u003e\u003cspan address=\"10.1186/s12935-021-02396-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eX T, Y Y (2023) Focal adhesion kinase: from biological functions to therapeutic strategies. Experimental Hematol Oncol 12(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s40164-023-00446-7\u003c/span\u003e\u003cspan address=\"10.1186/s40164-023-00446-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNazemi M, Yanes B, Martinez ML et al (2024) The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. PLoS Biol 22(1):e3002406. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pbio.3002406\u003c/span\u003e\u003cspan address=\"10.1371/journal.pbio.3002406\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZ Y (2023) Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol Cancer 22(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12943-023-01744-8\u003c/span\u003e\u003cspan address=\"10.1186/s12943-023-01744-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, Young patients, Immune microenvironment, Tumor-infiltrating immune cells, Gene expression","lastPublishedDoi":"10.21203/rs.3.rs-5382194/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5382194/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBreast cancer remains a prevalent malignancy worldwide, particularly affecting younger women more aggressively. Significant differences in clinical and biological characteristics exist between breast cancer with young patients (BCY) and breast cancer with non-young patients (BCNY). However, the role of the immune microenvironment in these differences is not fully understood.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eData from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database were analyzed to compare tumor-infiltrating immune cells (TIICs) and gene expression between BCY and BCNY. The CIBERSORT algorithm was used to estimate the relative abundance of 22 immune cell types, and differentially expressed genes (DEGs) were identified using the \"limma\" package in R.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe BCY group had a higher prevalence of M0 macrophages and activated dendritic cells, while the BCNY group exhibited greater infiltration of CD4 memory T cells, M2 macrophages, and neutrophils. Differential gene expression analysis identified 11 significantly expressed genes between the groups, with genes such as FDCSP and GABRP upregulated in the BCY group. GSEA revealed that pro-inflammatory pathways, such as cytokine-cytokine receptor interaction, were enriched in the BCY group, while pathways related to metabolism and extracellular matrix interactions were enriched in the BCNY group. Kaplan-Meier analysis demonstrated that high expression of certain genes, such as NAT1, CA12, and SRARP, was associated with better relapse-free survival.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBCY exhibit a distinct immune landscape characterized by higher levels of pro-inflammatory immune cells and pathways, contributing to a more aggressive disease profile.\u003c/p\u003e","manuscriptTitle":"Distinct Immune Landscape and Gene Expression Profiles in Breast Cancer: Young vs. Non-Young Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 15:49:48","doi":"10.21203/rs.3.rs-5382194/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fa019a5a-81e2-4fed-96f4-4553bff333f7","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-08T18:38:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-02 15:49:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5382194","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5382194","identity":"rs-5382194","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}