Greater Body Fatness is Associated with Higher Protein Expression of LEPR in Breast Tumor Tissues: Cross-Sectional Analysis in the Women’s Circle of Health Study

Greater Body Fatness is Associated with Higher Protein Expression of LEPR in Breast Tumor Tissues: Cross-Sectional Analysis in the Women’s Circle of Health Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Greater Body Fatness is Associated with Higher Protein Expression of LEPR in Breast Tumor Tissues: Cross-Sectional Analysis in the Women’s Circle of Health Study Adana A.M. Llanos, John B. Aremu, Ting-Yuan David Cheng, Wenjin Chen, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1374841/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 The molecular mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their respective receptors in the breast tumor microenvironment may play a role. Methods In a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index, and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin receptor (LEPR) and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons. Results In multivariable models, we found that increasing BMI (β = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β = 0.0015, 95% CI: 0.0007, 0.0024), and fat mass index (β = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These findings reflect a 16.8%, 17.6%, 17.7%, 17.2% increase in LEPR protein expression for each standard deviation increase in BMI, waist circumference, hip circumference, and fat mass index, respectively. These associations were stronger among White and postmenopausal women and ER + cases; formal tests of interaction yielded evidence of effect modification by race. We found no associations of any measure of body fatness with LEPR gene expression or with gene or protein expression of ADIPOR1 and ADIPOR2. Conclusions These findings support an association of increased body fatness – beyond overall body size measured using BMI – with higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step. adiposity breast cancer leptin receptor adiponectin receptor 1 adiponectin receptor 2 protein expression gene expression breast tumor tissues Introduction Epidemiologic evidence suggests that increasing obesity, measured using body mass index (BMI), is associated with elevated risk of postmenopausal breast cancer ( 1 , 2 ) and poorer breast cancer outcomes among both pre- and postmenopausal women ( 2 – 4 ). However, differences have been observed by estrogen receptor (ER) status ( 3 , 5 ). While increased premenopausal obesity is associated with increased risk of ER- but not ER + disease, postmenopausal obesity is similarly associated with increased risk of both ER- and ER + disease ( 5 , 6 ). On the other hand, increasing waist-to-hip ratio (WHR) is associated with increased risk of ER + disease among premenopausal women and with increased risk of both ER + and ER- disease among postmenopausal women ( 7 ). While the molecular mechanisms underlying the impact of overall and central obesity on poorer breast cancer outcomes are not well understood, it has been hypothesized that the biological effects of the adipokines, adiponectin (ADIPOQ) and leptin (LEP), which are secreted by adipocytes ( 8 – 13 ), and their respective receptors (adiponectin receptors 1 and 2 [ADIPOR1, ADIPOR2] and leptin receptor [LEPR], respectively) might play a role. Further, exploration of the relationship between central adiposity (rather than overall body size as measured by BMI) and adipokines and adipokine receptors might be the missing link. Circulating ADIPOQ levels decrease with increasing BMI ( 14 – 16 ) and are associated with increased breast cancer risk ( 17 – 20 ). Conversely, circulating LEP levels increase with increasing BMI ( 21 , 22 ) and are associated with increased breast cancer risk in some studies ( 17 , 23 – 25 ). Less is known about adipokine receptor protein and gene expression levels in breast tumor tissues or their associations with more accurate and specific measures of body fatness derived from anthropometry (e.g., waist circumference, hip circumference, waist-to-hip ratio [WHR]) or from bioelectrical impedance analysis (BIA) (e.g., fat mass index, percent body fat). These data might provide novel insights about the impact of body fatness and adiposity-related biomarker expression (at the tumor level) on breast cancer outcomes. ADIPOQ is the most abundantly secreted adipokine by adipocytes ( 15 , 26 ), and along with its receptors, is expressed in histologically normal and malignant breast tissues ( 27 , 28 ). ADIPOQ has anti-inflammatory and anti-atherogenic properties,( 26 , 29 ) inhibits cellular proliferation, and promotes apoptosis ( 10 , 13 , 30 ), implying a protective role in breast carcinogenesis. LEP, also secreted by adipocytes, is expressed in histologically normal and malignant breast cells, as is the LEPR ( 31 , 32 ), LEP, once bound to LEPR, induces the activation of several signaling pathways, promotes cell growth and proliferation, and promotes angiogenesis ( 33 – 38 ). Data from our prior research were the first to examine correlations between circulating ADIPOQ and LEP levels in plasma and levels within the breast, demonstrating that circulating adipokine levels are generally poor surrogates for levels within the local organ ( 39 ). More recently, we demonstrated that adipokine and adipokine receptor protein and gene expression in breast tumor tissues are associated with more aggressive tumor features associated with worse prognosis ( 40 , 41 ). Specifically, lower LEPR protein expression was associated with ER- status, triple-negative (TN) subtype ( 40 ), while lower gene expression of ADIPOQ , ADIPOR2 , LEP , and LEPR were associated with more aggressive breast tumor features, including higher tumor grade, larger tumor size, ER- status, and human epidermal growth factor receptor 2 (HER2)-enriched and TN subtypes ( 41 ). In the current study, we hypothesize that measures of body fatness are associated with LEPR , ADIPOR1 , and ADIPOR2 expression profiles in the breast tumor microenvironment, which might contribute mechanistically to the development of more aggressive breast tumor phenotypes and poorer prognosis. To test this, we investigated associations of general obesity (BMI), body fat distribution (waist circumference, hip circumference, WHR), and body composition (fat mass index, percent body fat) with protein and gene expression of the adipokine receptors in breast tissue specimens from participants in the Women’s Circle of Health Study (WCHS). Methods Study sample and data collection Study participants were women diagnosed with primary invasive breast cancer from 2001 through 2015 and enrolled in the WCHS ( 40 , 41 ). Briefly, WCHS enrolled newly diagnosed breast cancer cases with histologically confirmed ductal carcinoma in situ (DCIS, stage 0) or invasive breast cancer (stages I–IV), who self-identified as either Black/African American or White, were 20–75 years of age, able to complete an interview in English, and had no history of cancer except non-melanomatous skin cancer, were eligible to participate. Data collection for the WCHS was conducted through in-person assessments (approximately 10 months after diagnosis) and included computer-assisted interviewer-administered questionnaires, as well as standardized protocols for taking anthropometric measurements during a home visit, including height, weight, waist circumference, and hip circumference, and body composition using a portable BIA scale ( 42 ). The baseline interview ascertained information on sociodemographic factors as well as established or probable breast cancer risk factors, including: family and personal health history, reproductive history, hormone therapy use, and lifestyle exposures. Nearly all WCHS participants (98%) consented to medical records release and for these participants, medical and pathology records were requested and retrieved from providers and institutions where participants reported receiving breast cancer care. Relevant clinical and breast tumor clinicopathologic data were abstracted and entered in an electronic database ( 43 , 44 ). Collection of archived breast tumor specimens and tissue microarray construction Tumor blocks and/or slides for WCHS participants were retrieved from hospitals upon written consent, with a retrieval rate of approximately 85%. Upon receipt at the Data Bank and Biorepository (DBBR) at Roswell Park Comprehensive Cancer Center, a board-certified pathologist (TK) reviewed hematoxylin and eosin (H&E) slides and circled areas where cores were selected for tissue microarray (TMA) construction. TMA cores ranged in size from 0.6 mm to 1.2 mm in diameter, and most WCHS participants’ tumors were represented by at least two TMA cores (range: 1 to 6 cores), which were placed into a recipient formalin-fixed paraffin-embedded (FFPE) block. The location of each core was recorded in a detailed TMA map file. The completed TMAs were stored at room temperature. Protein expression analysis For each WCHS participant included in the protein expression analysis (n = 722), IHC was used to stain TMAs of breast tumor specimens for LEPR, ADIPOR1, and ADIPOR2 as previously described ( 40 ). A digital pathology analysis platform (VisioPharm, Hoersholm Denmark) was used to quantify protein expression of the adipokine receptors on each tissue core ( 45 ). Quantitative results were reported as a protein expression score defined as effective staining intensity (ESI) within the effective staining area (ESA) ( 45 ). Specimen artifacts, such as tissue folding were manually excluded from quantification. A board-certified pathologist (MAC) semi-quantitatively evaluated IHC expression for each tissue core stained ( 45 ). Semi-quantitative expression results were reported as: 0 (negative), 1 (weak expression), 2 (moderate expression), or 3 (strong expression). There was high concordance between unsupervised, quantitative scores and pathologist-generated, semi-quantitative scores for LEPR (r = 0.71, P < 0.0001) ( 40 ). In the present analysis we included only quantitative protein expression data for LEPR, ADIPOR1, and ADIPOR2, which were averaged for participants with multiple TMA cores. Log-transformed protein expression data were used in the subsequent analysis. Gene expression analysis For each WCHS participant included in the gene expression analysis (n = 148), RNA was extracted from two 10µm curls (from representative breast tumor blocks without any pre-selection based on either the tumor or stromal contents so as to maintain and capture the entire tumor lesion and surrounding microenvironment) using the High Pure FFPET RNA Isolation Kit (Roche Molecular Systems, Inc., Pleasanton, CA, USA) and quantified using Qubit and Agilent Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA). Gene expression of ADIPOR1 , ADIPOR2 , and LEPR were quantitated using NanoString nCounter® technology (NanoString Technologies, Seattle, WA, USA) ( 41 ). Raw count data were subjected to a series of normalization steps, including positive controls, housekeeping genes, and background subtraction, and the normalized data were log2-transformed and used in subsequent analyses ( 41 ). Statistical Analyses Descriptive statistics (mean and standard deviation [SD] and frequency and proportions) were used to describe the study sample and Pearson’s correlation analysis was used to assess pairwise correlations between adipokine receptor protein and gene expression. Multivariable linear regression models were utilized to evaluate the associations of BMI, waist circumference, hip circumference, WHR, fat mass index, and percent body fat with protein and gene expression of LEPR, ADIPOR1, and ADIPOR2. The difference in protein and gene expression per increase in SD of body fatness measures was also estimated, and a percentage increase was estimated as [exp(beta) -1] x 100%. Models were adjusted for race, menopausal status, and ER status. All reported P -values are two-sided and P < 0.05 was considered statistically significant. To account for multiple comparisons, we used Bonferroni correction with a criterion of P < 0.0083 (i.e., 0.05/6) for statistical significance, given that there were six tests of association for protein and gene expression of each marker of interest. Analyses were performed using STATA (version 17, StataCorp, College Station, TX). Results Sociodemographic and tumor characteristics of the study sample included in the protein expression and the gene expression analytic samples are shown in Table 1 . Across both groups, most participants met the criteria for increased metabolic risk(46, 47) based on overall obesity (BMI >30 kg/m 2 [50.6%]), central obesity (waist circumference >88 cm [74.4%] and/or WHR >0.85 [64.1%]), elevated/abnormal fat mass index (³9.5 kg/m 2 [73.4%]), and percent body fat (>35% [76.2%]). Table 1. Select characteristics of analytic samples included in the adipokine receptor protein expression and gene expression analysis Protein expression, N = 722 a Gene expression, N = 148 b Sociodemographic and clinical characteristics n (%) n (%) Age at diagnosis (years), mean±SD 52.58 ± 10.83 53.08 ± 10.34 Menopausal status Premenopausal 325 (46.43) 68 (47.22) Postmenopausal 375 (53.57) 76 (52.78) Race Black/African American 541 (77.29) 109 (75.69) White 159 (22.71) 35 (24.31) Body mass index (kg/m 2 ), mean±SD 30.72±6.99 30.89±7.50 Waist circumference (cm), mean±SD 98.63±15.47 99.15±15.66 Hip circumference (cm), mean±SD 112.13±13.30 111.86±13.88 Waist-to-hip ratio, mean±SD 0.87±0.08 0.88±0.07 Fat mass index, mean±SD 12.44±4.82 12.61±5.27 Percent body fat (%),mean±SD 39.30±7.77 39.20±8.07 Breast tumor characteristics Tumor grade Well differentiated 107 (16.85) 13 (9.03) Moderately differentiated 219 (34.49) 45 (31.25) Poorly differentiated 309 (48.66) 86 (59.72) Tumor size 2.0 cm 292 (40.44) 62 (41.89) AJCC stage Stage 0 62 (8.96) 1 (0.72) Stage I 257 (37.14) 54 (39.13) Stage II 271 (39.16) 66 (47.83) Stage III 96 (13.87) 14 (10.14) Stage IV 6 (0.87) 3 (2.17) ER status ER+ 505 (70.14) 84 (56.76) ER- 215 (29.86) 64 (43.24) HER2 status HER2- 412 (81.58) 112 (75.68) HER2+ 93 (18.42) 36 (24.32) a In the protein expression sample, age was missing for 22 (3%); BMI was missing for 23 (3.2%); waist circumference, hip circumference, and waist-to-hip ratio were missing for 33 (4.6%); fat mass index was missing for 66 (9.1%); percent body fat was missing for 64 (8.9%); tumor grade was missing for 87 (12%); tumor stage was missing for 30 (4.2%); ER status was missing for 2 (0.3%), and HER2 status was missing for 18 (2.5%) participants. b In the gene expression sample, age, menopausal status, race, and BMI was missing for 4 (2.7%) participants; waist circumference, hip circumference, and waist-to-hip ratio were missing for 5 (3.4%) participants; fat mass index and percent body fat were missing for 12 (8.1%) participants; tumor grade was missing for 4 (2.7%) participants; and tumor stage was missing for 10 (6.8%) participants. There was a weak positive correlation between LEPR protein and LEPR gene expression (r = 0.29, P = 0.0006), no significant correlation between ADIPOR1 protein and ADIPOR1 gene expression (r = -0.03, P = 0.69), and a very weak positive correlation between ADIPOR2 protein and ADIPOR2 gene expression (r = 0.18, P = 0.04). In models adjusting for race, menopausal status, and ER status, we found that women with greater body fatness had significantly higher LEPR protein expression: BMI (b = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (b = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (b = 0.0015, 95% CI: 0.0007, 0.0024), and fat mass index (b = 0.0041, 95% CI: 0.0015, 0.0067) ( Table 2 ). These findings, which were significant with correction for multiple comparisons, equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for each standard deviation increase in BMI, waist circumference, hip circumference, and fat mass index, respectively. WHR was not associated with LEPR protein expression. Upon further adjustment for waist circumference, the observed associations between BMI (P = 0.08), hip circumference (P = 0.13), and percent body fat (P = 0.26) were consistent but attenuated, while the association for fat mass index was slightly stronger (b = 0.0055, 95% CI: 0.0005, 0.0010; 24.1% increase in LEPR protein expression), although not statistically significant (data not shown). Conversely, we found no association between body fatness and LEPR gene expression. Associations between body fatness and ADIPOR1 expression ( Table 3 ) and ADIPOR2 expression ( Table 4 ) were also not statistically significant, but the coefficients suggested that increasing body fatness might be associated with lower protein expression and higher gene expression. Table 2. Multivariable-adjusted associations of body fatness measures with LEPR protein and LEPR gene expression in breast tumor tissues. LEPR protein expression LEPR gene expression n β (95% CI) β standardized P n β (95% CI) β standardized P Body mass index (kg/m 2 ) 571 0.0028 (0.0011, 0.0045) 0.155 0.002** 144 0.0062 (-0.0187, 0.0312) 0.053 0.625 Waist circumference (cm) 561 0.0013 (0.0005, 0.0022) 0.162 0.001** 143 -0.0003 (-0.0122, 0.0116) -0.005 0.962 Hip circumference (cm) 561 0.0015 (0.0007, 0.0024) 0.163 0.001** 143 -0.0006 (-0.0134, 0.0122) -0.009 0.927 Waist-to-hip ratio 561 0.0537 (-0.1131, 0.2206) 0.033 0.528 143 -0.1725 (-2.8365, 2.4914) -0.014 0.899 Fat mass index (kg/m 2 ) 534 0.0041 (0.0015, 0.0067) 0.159 0.002** 136 0.0091 (-0.0275, 0.0458) 0.055 0.626 Percent body fat (%) 536 0.0020 (0.0004, 0.0036) 0.124 0.016* 136 -0.0012 (-0.0246, 0.0228) -0.008 0.941 NOTE: Protein expression scores reflect quantitative protein expression (using immunohistochemistry) of LEPR as analyzed through an automated/unsupervised scoring (quantitative) methodology. The scores estimate the effective staining intensity (ESI) within the effective staining area (ESA) of the biomarker in question (mean±SD of log-transformed values are shown). Gene expression scores reflect normalized, log2-transformed gene expression of LEPR as analyzed through the Nanostring nCounter Analysis System. Each model was generated using multiple linear regression adjusting for race, menopausal status, and estrogen receptor status. * Statistically significant at P<0.05; ** Statistically significant with correction for multiple comparisons (P <0.0083). Table 3. Multivariable-adjusted associations of body fatness measures with ADIPOR1 protein and ADIPOR1 gene expression in breast tumor tissues. ADIPOR1 protein expression ADIPOR1 gene expression n β (95% CI) β standardized P n β (95% CI) β standardized P Body mass index (kg/m 2 ) 665 -0.0008 (-0.0028, 0.0013) -0.035 0.473 144 0.0070 (-0.0045, 0.0184) 0.128 0.234 Waist circumference (cm) 654 -0.0002 (-0.0011, 0.0008) -0.015 0.761 143 0.0048 (-0.0007, 0.0102) 0.181 0.090 Hip circumference (cm) 654 -0.0004 (-0.0014, 0.0007) -0.032 0.497 143 0.0032 (-0.0032, 0.0086) 0.091 0.367 Waist-to-hip ratio 654 0.0474 (-0.1447, 0.2394) 0.024 0.629 143 1.1785 (-0.0507, 2.4078) 0.212 0.062 Fat mass index (kg/m 2 ) 624 -0.0019 (-0.0050, 0.0013) -0.059 0.249 136 0.0081 (-0.0091, 0.0252) 0.104 0.357 Percent body fat (%) 626 -0.0016 (-0.0036, 0.0003) -0.083 0.099 136 0.0045 (-0.0066, 0.0156) 0.090 0.424 NOTE: Protein expression scores reflect quantitative protein expression (using immunohistochemistry) of ADIPOR1 as analyzed through an automated/unsupervised scoring (quantitative) methodology. The scores estimate the effective staining intensity (ESI) within the effective staining area (ESA) of the biomarker in question (mean±SD of log-transformed values are shown). Gene expression scores reflect normalized, log2-transformed gene expression of ADIPOR1 as analyzed through the Nanostring nCounter Analysis System. Each model was generated using multiple linear regression adjusting for race, menopausal status, and estrogen receptor status. Table 4. Multivariable-adjusted associations of body fatness measures with ADIPOR2 protein and ADIPOR2 gene expression in breast tumor tissues. ADIPOR2 protein expression ADIPOR2 gene expression n β (95% CI) β standardized P n β (95% CI) β standardized P Body mass index (kg/m 2 ) 584 -0.0003 (-0.0028, 0.0023) -0.010 0.844 144 0.0098 (-0.0103, 0.0300) 0.100 0.346 Waist circumference (cm) 575 -0.0003 (-0.0015, 0.0009) -0.029 0.585 143 0.0085 (-0.0012, 0.0182) 0.182 0.088 Hip circumference (cm) 575 -0.0001 (-0.0014, 0.0012) -0.008 0.873 143 0.0046 (-0.0058, 0.0150) 0.087 0.387 Waist-to-hip ratio 575 -0.0389 (-0.2773, 0.1995) -0.017 0.749 143 2.1901 (0.0181, 4.3621) 0.221 0.050 Fat mass index (kg/m 2 ) 552 0.0002 (-0.0037, 0.0040) 0.004 0.939 136 0.0155 (-0.0146, 0.0456) 0.113 0.313 Percent body fat (%) 554 0.0007 (-0.0017, 0.0031) 0.031 0.557 136 0.0136 (-0.0058, 0.0330) 0.151 0.171 NOTE: Protein expression scores reflect quantitative protein expression (using immunohistochemistry) of ADIPOR2 as analyzed through an automated/unsupervised scoring (quantitative) methodology. The scores estimate the effective staining intensity (ESI) within the effective staining area (ESA) of the biomarker in question (mean±SD of log-transformed values are shown). Gene expression scores reflect normalized, log2-transformed gene expression of ADIPOR2 as analyzed through the Nanostring nCounter Analysis System. Each model was generated using multiple linear regression adjusting for race, menopausal status, and estrogen receptor status. Given the multivariable-adjusted associations observed between measures of body fatness and LEPR protein expression levels, we explored potential differences by race ( Table S1 ), menopausal status ( Table S2 ), and ER status ( Table S3 ). Qualitatively, our observation that increasing body fatness measures are associated with higher LEPR protein expression appeared stronger among White women, postmenopausal women, and ER+ cases. Formal tests of interaction yielded statistically significant evidence of effect modification by race for some body fatness measures (BMI, P = 0.041; fat mass index, P = 0.016; and percent body fat, P = 0.019), but not others (waist circumference, P = 0.080; hip circumference, P = 0.086) (data not shown). However, we observed no evidence of effect modification by menopausal status (P-values for all body fatness measures >0.05), and limited evidence of effect modification by ER status (BMI, P = 0.318; waist circumference, P = 0.093; hip circumference, P = 0.059; WHR, P = 0.821; fat mass index, P = 0.250; and percent body fat, P = 0.553) (data not shown). Discussion Building on our prior research, here we examined the association of body fatness measures with protein and gene expression of the adipokine receptors, LEPR, ADIPOR1, and ADIPOR2 in the breast tumor microenvironment. To our knowledge, this is the first study to investigate these associations in women with breast cancer. Partially consistent with our hypothesis, greater body fatness is associated with increased LEPR protein expression, although we observed no association between body fatness and LEPR gene expression, nor with protein or gene expression of ADIPOR1 and ADIPOR2. Past studies show that BMI is positively associated with circulating leptin concentrations and inversely associated with circulating adipokine concentrations, which are associated with increased risk of some obesity-related cancers including breast cancer (reviewed by Yoon et al ( 48 )). Our findings that increasing measures of body fatness are positively associated with LEPR protein expression in breast tumors independent of age and menopausal status (with correction for multiplicity) support the hypothesis that LEPR protein expression in breast tumor tissues play a role in breast carcinogenesis ( 49 – 54 ). Interestingly, our analysis showed significant effect modification by race (stronger among White women) and marginally significant effect modification by ER status (suggestion of stronger associations among ER + cases, although our analysis was underpowered given the small sample of ER- cases). These findings further highlight the complex interplay among LEPR protein expression, adiposity, race, and breast tumor phenotype ( 55 – 58 ), which might require more precise adiposity measures, and identification and refinement of adiposity-associated biomarkers within breast tumor tissues that can predict breast cancer outcomes. We observed no significant associations between body fatness and LEPR gene expression, but we previously showed that gene expression of LEPR is significantly lower in ER- and TN breast tumors relative to ER + and luminal A subtypes, respectively ( 41 ). While our sample with data on adipokine receptor gene expression was small and limited our statistical power, larger studies in the future will help clarify these findings. Nonetheless, our findings suggest that distribution of adiposity and adiposity-related expression profiles of LEPR, ADIPOR1, and ADIPOR2 in the local organ might have differential impacts on breast cancer based on tumor subtype, and the crosstalk between ER and adipokine biomarkers and other inflammatory biomarkers might play a role ( 59 ). Prior analysis from WCHS reported a lack of association between BMI and breast cancer risk, but higher hip circumference and waist circumference were associated with more than 2-fold increased risk of pre-menopausal breast cancer among women in the fourth quartiles for each measure compared to the first quartile. 42 Further, findings from WCHS also showed that compared to BMI, WHR had a stronger association with overall and breast cancer-specific mortality among Black women. Specifically, compared to the first quartile, women in the fourth quartile of WHR had 61% and 68% increased risk of overall and breast cancer specific death, respectively, while women with class I and class II obesity (compared to normal weight) had statistically non-significant increased risk of death ranging from 17—33% ( 44 ). From the combination of these findings, investigations of the associations between more accurate measures of adiposity and distribution (including overall adiposity, visceral adiposity, and subcutaneous adiposity assessed through computed tomography [CT]), in association with adipokine receptor protein and gene expression are critical to elucidating the impact of adiposity on breast carcinogenesis and progression. An important strength of this study is that it adds to knowledge regarding the potential impact of overall and central body fatness on adiposity-related biomarkers in breast tumor tissues. Our findings suggest that measures of body fatness are associated with the expression of adipokine receptors – primarily LEPR – in breast tumors. From this, we generated new hypotheses about the mechanisms linking central adiposity with breast cancer outcomes, which will be pursued. Another strength was the opportunity to perform stratified analysis of the associations of interest by ER status, yielding novel findings. Lastly, was our population-based sample that included a large proportion of Black women with breast cancer was also a strength. This study also has some limitations worth noting, including a relatively small sample size (particularly in the gene expression analysis [n = 148]), which may have reduced the power to detect meaningful associations and limit our ability to fully evaluate the complex associations of body fatness and breast cancer. Relatedly, our analysis included multiple comparisons which may have increased the likelihood of observing statistically significant associations. However, we addressed this concern using Bonferroni correction. Despite these limitations, the findings substantiated our hypothesis that measures of body fatness are associated with protein expression of the adipokine receptors (namely, LEPR) in the breast tumor microenvironment. These data are an important step towards understanding the biologic effects of and potential mechanisms linking adiposity with breast cancer risk and prognosis. Abbreviations ADIPOQ: adiponectin ADIPOR1: adiponectin receptor 1 ADIPOR2: adiponectin receptor 2 BIA: bioelectrical impedance analysis BMI: body mass index CI: confidence interval CT: computed tomography DCIS: ductal carcinoma in situ ER: estrogen receptor ESA: effective staining area ESI: effective staining intensity FFPE: formalin-fixed paraffin-embedded H&E: hematoxylin and eosin HER2: human epidermal growth factor receptor 2 LEPR: leptin receptor SD: standard deviation TMA: tissue microarray TMA-AID: TN: triple negative WCHS: Women’s Circle of Health Study WHR: waist-to-hip ratio Declarations Ethics approval and consent to participate This study received ethics approval from the Rutgers University Institutional Review Board. All study methods were carried out in accordance with the requirements of the United States Common Rule (45CFR 46, U.S. Department of Health & Human Services [HHS], Office for Human Research Protections [OHRP]). All study participants provided written informed consent prior to study enrollment. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported by funding from the National Cancer Institute of the National Institutes of Health under the following award numbers: K01CA193527 (awarded to A.A.M. Llanos), P01CA151135 (awarded to C.B. Ambrosone), P30CA072720 (awarded to S. Libutti), R01CA100598 (awarded to C.B. Ambrosone), R01CA185623 (awarded to E.V. Bandera, K. Demissie, and C.C. Hong), K08CA172722 (awarded to C. Omene), K07CA201334 (awarded to T-Y.D. Cheng), and K01CA226155 (awarded to EMC. Feliciano). Support was also received by the U.S. Army Medical Research and Development Command under award number DAMD‐17‐01‐1‐0334 (awarded to D.H. Bovbjerg), the Breast Cancer Research Foundation (awarded to C.B. Ambrosone and C.C. Hong), and a gift from the Philip L. Hubbell Family (awarded to C.B. Ambrosone). Tumor samples were received, processed and tracked under the auspices of the Roswell Park Comprehensive Cancer Center Data Bank and BioRepository Shared Resource, with funding from NCI-CCSG P30CA16056. Services, results and/or products in support of this research project were generated using the Rutgers Cancer Institute of New Jersey Biomedical Informatics Shared Resource (P30CA072720-5917) and the Biospecimen Repository and Histopathology Service Shared Resource (P30CA072720-5919). The New Jersey State Cancer Registry is funded by the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program (#75N91021D00009), Centers for Disease Control and Prevention’s National Program of Cancer Registries (#5NU58DP006279) with additional support from the State of New Jersey and the Rutgers Cancer Institute of New Jersey. Authors' contributions AAML: grant funding, study conception and design, data collection, data analysis, data interpretation, and writing; JBA: literature search and data interpretation. TDC: data interpretation and manuscript editing; WC: data collection and manuscript editing. MAC: pathology review, data collection, and manuscript editing. EMCF: data interpretation and manuscript editing. BQ: data collection, data interpretation, and manuscript editing. YL: data analysis, data interpretation, and manuscript editing. CO: data interpretation and manuscript editing. TK: pathology review, data collection, and manuscript editing. CH: grant funding, data collection, and manuscript editing. SY: data collection, data interpretation, and manuscript editing. CBA: grant funding, data collection, data interpretation, and manuscript editing. EVB: grant funding, data collection, data interpretation, and manuscript editing. KD: grant funding, data collection, data interpretation, and manuscript editing. All authors read and approved the final manuscript. Acknowledgements We are sincerely appreciative of the breast cancer advocates, community partners, and all study participants who made this work possible. We are equally grateful to the highly motivated, hardworking research personnel of the Women’s Circle of Health Study at the Rutgers School of Public Health, Rutgers Cancer Institute of New Jersey, Roswell Park Comprehensive Cancer Center, Mount Sinai School of Medicine (now Icahn School of Medicine at Mount Sinai), and the New Jersey State Cancer Registry. 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Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP. Leptin is a growth factor for colonic epithelial cells. Gastroenterology. 2001;121(1):79–90. Laud K, Gourdou I, Pessemesse L, Peyrat JP, Djiane J. Identification of leptin receptors in human breast cancer: functional activity in the T47-D breast cancer cell line. Mol Cell Endocrinol. 2002;188(1–2):219–26. Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A. 2001;98(11):6390–5. Park HY, Kwon HM, Lim HJ, Hong BK, Lee JY, Park BE, et al. Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. Exp Mol Med. 2001;33(2):95–102. Somasundar P, McFadden DW, Hileman SM, Vona-Davis L. Leptin is a growth factor in cancer. J Surg Res. 2004;116(2):337–49. Llanos AA, Dumitrescu RG, Marian C, Makambi KH, Spear SL, Kallakury BV, et al. Adipokines in plasma and breast tissues: associations with breast cancer risk factors. Cancer Epidemiol Biomarkers Prev. 2012;21(10):1745–55. Llanos AAM, Lin Y, Chen W, Yao S, Norin J, Chekmareva MA, et al. Immunohistochemical analysis of adipokine and adipokine receptor expression in the breast tumor microenvironment: associations of lower leptin receptor expression with estrogen receptor-negative status and triple-negative subtype. Breast Cancer Res. 2020;22(1):18. Llanos AAM, Yao S, Singh A, Aremu JB, Khiabanian H, Lin Y, et al. Gene expression of adipokines and adipokine receptors in the tumor microenvironment: associations of lower expression with more aggressive breast tumor features. Breast Cancer Res Treat. 2020. Bandera EV, Chandran U, Zirpoli G, Gong Z, McCann SE, Hong CC, et al. Body fatness and breast cancer risk in women of African ancestry. BMC cancer. 2013;13:475. George P, Chandwani S, Gabel M, Ambrosone CB, Rhoads G, Bandera EV, et al. Diagnosis and surgical delays in African American and white women with early-stage breast cancer. J Womens Health (Larchmt). 2015;24(3):209–17. Bandera EV, Qin B, Lin Y, Zeinomar N, Xu B, Chanumolu D, et al. Association of Body Mass Index, Central Obesity, and Body Composition With Mortality Among Black Breast Cancer Survivors. JAMA Oncol. 2021. Chen W, Reiss M, Foran DJ. A prototype for unsupervised analysis of tissue microarrays for cancer research and diagnostics. IEEE Trans Inf Technol Biomed. 2004;8(2):89–96. World Health Organization. Waist circumference and waist-hip ratio: a report of a WHO expert consultation. Geneva, 2011. Peltz G, Aguirre MT, Sanderson M, Fadden MK. The role of fat mass index in determining obesity. Am J Hum Biol. 2010;22(5):639–47. Yoon YS, Kwon AR, Lee YK, Oh SW. Circulating adipokines and risk of obesity related cancers: A systematic review and meta-analysis. Obes Res Clin Pract. 2019;13(4):329–39. Jarde T, Perrier S, Vasson MP, Caldefie-Chezet F. Molecular mechanisms of leptin and adiponectin in breast cancer. Eur J Cancer. 2011;47(1):33–43. Ishikawa M, Kitayama J, Nagawa H. Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res. 2004;10(13):4325–31. Fiorio E, Mercanti A, Terrasi M, Micciolo R, Remo A, Auriemma A, et al. Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis. BMC cancer. 2008;8:305. Kim Y, Kim SY, Lee JJ, Seo J, Kim YW, Koh SH, et al. Effects of the expression of leptin and leptin receptor (OBR) on the prognosis of early-stage breast cancers. Cancer Res Treat. 2006;38(3):126–32. Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res. 2006;12(5):1447–53. Jarde T, Caldefie-Chezet F, Damez M, Mishellany F, Penault-Llorca F, Guillot J, et al. Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol Rep. 2008;19(4):905–11. Suzuki R, Orsini N, Saji S, Key TJ, Wolk A. Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status–a meta-analysis. Int J Cancer. 2009;124(3):698–712. van den Brandt PA, Spiegelman D, Yaun SS, Adami HO, Beeson L, Folsom AR, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol. 2000;152(6):514–27. Yang XR, Chang-Claude J, Goode EL, Couch FJ, Nevanlinna H, Milne RL, et al. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst. 2011;103(3):250–63. Raut PK, Kim SH, Choi DY, Jeong GS, Park PH. Growth of breast cancer cells by leptin is mediated via activation of the inflammasome: Critical roles of estrogen receptor signaling and reactive oxygen species production. Biochem Pharmacol. 2019;161:73–88. Holm JB, Rosendahl AH, Borgquist S. Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer. Cancers (Basel). 2021;13(24). Additional Declarations No competing interests reported. Supplementary Files SupplementaryTables13.docx 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 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-1374841","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":84996688,"identity":"f7d30342-f854-48fd-a8f8-443acef46e8d","order_by":0,"name":"Adana A.M. 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However, differences have been observed by estrogen receptor (ER) status (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). While increased premenopausal obesity is associated with increased risk of ER- but not ER\u0026thinsp;+\u0026thinsp;disease, postmenopausal obesity is similarly associated with increased risk of both ER- and ER\u0026thinsp;+\u0026thinsp;disease (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). On the other hand, increasing waist-to-hip ratio (WHR) is associated with increased risk of ER\u0026thinsp;+\u0026thinsp;disease among premenopausal women and with increased risk of both ER\u0026thinsp;+\u0026thinsp;and ER- disease among postmenopausal women (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWhile the molecular mechanisms underlying the impact of overall and central obesity on poorer breast cancer outcomes are not well understood, it has been hypothesized that the biological effects of the adipokines, adiponectin (ADIPOQ) and leptin (LEP), which are secreted by adipocytes (\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), and their respective receptors (adiponectin receptors 1 and 2 [ADIPOR1, ADIPOR2] and leptin receptor [LEPR], respectively) might play a role. Further, exploration of the relationship between central adiposity (rather than overall body size as measured by BMI) and adipokines and adipokine receptors might be the missing link. Circulating ADIPOQ levels decrease with increasing BMI (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and are associated with increased breast cancer risk (\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Conversely, circulating LEP levels increase with increasing BMI (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) and are associated with increased breast cancer risk in some studies (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Less is known about adipokine receptor protein and gene expression levels in breast tumor tissues or their associations with more accurate and specific measures of body fatness derived from anthropometry (e.g., waist circumference, hip circumference, waist-to-hip ratio [WHR]) or from bioelectrical impedance analysis (BIA) (e.g., fat mass index, percent body fat). These data might provide novel insights about the impact of body fatness and adiposity-related biomarker expression (at the tumor level) on breast cancer outcomes.\u003c/p\u003e \u003cp\u003eADIPOQ is the most abundantly secreted adipokine by adipocytes (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), and along with its receptors, is expressed in histologically normal and malignant breast tissues (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). ADIPOQ has anti-inflammatory and anti-atherogenic properties,(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) inhibits cellular proliferation, and promotes apoptosis (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), implying a protective role in breast carcinogenesis. LEP, also secreted by adipocytes, is expressed in histologically normal and malignant breast cells, as is the LEPR (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), LEP, once bound to LEPR, induces the activation of several signaling pathways, promotes cell growth and proliferation, and promotes angiogenesis (\u003cspan additionalcitationids=\"CR34 CR35 CR36 CR37\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eData from our prior research were the first to examine correlations between circulating ADIPOQ and LEP levels in plasma and levels within the breast, demonstrating that circulating adipokine levels are generally poor surrogates for levels within the local organ (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). More recently, we demonstrated that adipokine and adipokine receptor protein and gene expression in breast tumor tissues are associated with more aggressive tumor features associated with worse prognosis (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Specifically, lower LEPR protein expression was associated with ER- status, triple-negative (TN) subtype (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), while lower gene expression of \u003cem\u003eADIPOQ\u003c/em\u003e, \u003cem\u003eADIPOR2\u003c/em\u003e, \u003cem\u003eLEP\u003c/em\u003e, and \u003cem\u003eLEPR\u003c/em\u003e were associated with more aggressive breast tumor features, including higher tumor grade, larger tumor size, ER- status, and human epidermal growth factor receptor 2 (HER2)-enriched and TN subtypes (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the current study, we hypothesize that measures of body fatness are associated with \u003cem\u003eLEPR\u003c/em\u003e, \u003cem\u003eADIPOR1\u003c/em\u003e, and \u003cem\u003eADIPOR2\u003c/em\u003e expression profiles in the breast tumor microenvironment, which might contribute mechanistically to the development of more aggressive breast tumor phenotypes and poorer prognosis. To test this, we investigated associations of general obesity (BMI), body fat distribution (waist circumference, hip circumference, WHR), and body composition (fat mass index, percent body fat) with protein and gene expression of the adipokine receptors in breast tissue specimens from participants in the Women\u0026rsquo;s Circle of Health Study (WCHS).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy sample and data collection\u003c/h2\u003e \u003cp\u003eStudy participants were women diagnosed with primary invasive breast cancer from 2001 through 2015 and enrolled in the WCHS (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Briefly, WCHS enrolled newly diagnosed breast cancer cases with histologically confirmed ductal carcinoma in situ (DCIS, stage 0) or invasive breast cancer (stages I\u0026ndash;IV), who self-identified as either Black/African American or White, were 20\u0026ndash;75 years of age, able to complete an interview in English, and had no history of cancer except non-melanomatous skin cancer, were eligible to participate. Data collection for the WCHS was conducted through in-person assessments (approximately 10 months after diagnosis) and included computer-assisted interviewer-administered questionnaires, as well as standardized protocols for taking anthropometric measurements during a home visit, including height, weight, waist circumference, and hip circumference, and body composition using a portable BIA scale (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). The baseline interview ascertained information on sociodemographic factors as well as established or probable breast cancer risk factors, including: family and personal health history, reproductive history, hormone therapy use, and lifestyle exposures.\u003c/p\u003e \u003cp\u003eNearly all WCHS participants (98%) consented to medical records release and for these participants, medical and pathology records were requested and retrieved from providers and institutions where participants reported receiving breast cancer care. Relevant clinical and breast tumor clinicopathologic data were abstracted and entered in an electronic database (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCollection of archived breast tumor specimens and tissue microarray construction\u003c/h2\u003e \u003cp\u003e Tumor blocks and/or slides for WCHS participants were retrieved from hospitals upon written consent, with a retrieval rate of approximately 85%. Upon receipt at the Data Bank and Biorepository (DBBR) at Roswell Park Comprehensive Cancer Center, a board-certified pathologist (TK) reviewed hematoxylin and eosin (H\u0026amp;E) slides and circled areas where cores were selected for tissue microarray (TMA) construction. TMA cores ranged in size from 0.6 mm to 1.2 mm in diameter, and most WCHS participants\u0026rsquo; tumors were represented by at least two TMA cores (range: 1 to 6 cores), which were placed into a recipient formalin-fixed paraffin-embedded (FFPE) block. The location of each core was recorded in a detailed TMA map file. The completed TMAs were stored at room temperature.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eProtein expression analysis\u003c/h2\u003e \u003cp\u003eFor each WCHS participant included in the protein expression analysis (n\u0026thinsp;=\u0026thinsp;722), IHC was used to stain TMAs of breast tumor specimens for LEPR, ADIPOR1, and ADIPOR2 as previously described (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). A digital pathology analysis platform (VisioPharm, Hoersholm Denmark) was used to quantify protein expression of the adipokine receptors on each tissue core (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Quantitative results were reported as a protein expression score defined as effective staining intensity (ESI) within the effective staining area (ESA) (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Specimen artifacts, such as tissue folding were manually excluded from quantification. A board-certified pathologist (MAC) semi-quantitatively evaluated IHC expression for each tissue core stained (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Semi-quantitative expression results were reported as: 0 (negative), 1 (weak expression), 2 (moderate expression), or 3 (strong expression). There was high concordance between unsupervised, quantitative scores and pathologist-generated, semi-quantitative scores for LEPR (r\u0026thinsp;=\u0026thinsp;0.71, \u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.0001) (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). In the present analysis we included only quantitative protein expression data for LEPR, ADIPOR1, and ADIPOR2, which were averaged for participants with multiple TMA cores. Log-transformed protein expression data were used in the subsequent analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eGene expression analysis\u003c/h2\u003e \u003cp\u003eFor each WCHS participant included in the gene expression analysis (n\u0026thinsp;=\u0026thinsp;148), RNA was extracted from two 10\u0026micro;m curls (from representative breast tumor blocks without any pre-selection based on either the tumor or stromal contents so as to maintain and capture the entire tumor lesion and surrounding microenvironment) using the High Pure FFPET RNA Isolation Kit (Roche Molecular Systems, Inc., Pleasanton, CA, USA) and quantified using Qubit and Agilent Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA). Gene expression of \u003cem\u003eADIPOR1\u003c/em\u003e, \u003cem\u003eADIPOR2\u003c/em\u003e, and \u003cem\u003eLEPR\u003c/em\u003e were quantitated using NanoString nCounter\u0026reg; technology (NanoString Technologies, Seattle, WA, USA) (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Raw count data were subjected to a series of normalization steps, including positive controls, housekeeping genes, and background subtraction, and the normalized data were log2-transformed and used in subsequent analyses (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eDescriptive statistics (mean and standard deviation [SD] and frequency and proportions) were used to describe the study sample and Pearson\u0026rsquo;s correlation analysis was used to assess pairwise correlations between adipokine receptor protein and gene expression. Multivariable linear regression models were utilized to evaluate the associations of BMI, waist circumference, hip circumference, WHR, fat mass index, and percent body fat with protein and gene expression of LEPR, ADIPOR1, and ADIPOR2. The difference in protein and gene expression per increase in SD of body fatness measures was also estimated, and a percentage increase was estimated as [exp(beta) -1] x 100%. Models were adjusted for race, menopausal status, and ER status. All reported \u003cem\u003eP\u003c/em\u003e-values are two-sided and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. To account for multiple comparisons, we used Bonferroni correction with a criterion of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0083 (i.e., 0.05/6) for statistical significance, given that there were six tests of association for protein and gene expression of each marker of interest. Analyses were performed using STATA (version 17, StataCorp, College Station, TX).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eSociodemographic and tumor characteristics of the study sample included in the protein expression and the gene expression analytic samples are shown in \u003cstrong\u003eTable 1\u003c/strong\u003e. Across both groups, most participants met the criteria for increased metabolic risk(46, 47)\u0026nbsp;based on overall obesity (BMI \u0026gt;30 kg/m\u003csup\u003e2\u003c/sup\u003e [50.6%]), central obesity (waist circumference \u0026gt;88 cm [74.4%] and/or WHR \u0026gt;0.85 [64.1%]), elevated/abnormal fat mass index (\u0026sup3;9.5 kg/m\u003csup\u003e2\u003c/sup\u003e [73.4%]), and percent body fat (\u0026gt;35% [76.2%]).\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" width=\"100%\"\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eSelect characteristics of analytic samples included in the adipokine receptor protein expression and gene expression analysis\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtein\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;expression,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN = 722\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene expression,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN = 148\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003e\u003cem\u003eSociodemographic and clinical characteristics\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eAge at diagnosis (years), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e52.58 \u0026plusmn; 10.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e53.08 \u0026plusmn; 10.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eMenopausal status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003ePremenopausal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e325 (46.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e68 (47.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003ePostmenopausal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e375 (53.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e76 (52.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eRace\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eBlack/African American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e541 (77.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e109 (75.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e159 (22.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e35 (24.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e30.72\u0026plusmn;6.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e30.89\u0026plusmn;7.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eWaist circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e98.63\u0026plusmn;15.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e99.15\u0026plusmn;15.66\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eHip circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e112.13\u0026plusmn;13.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e111.86\u0026plusmn;13.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eWaist-to-hip ratio, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e0.87\u0026plusmn;0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e0.88\u0026plusmn;0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eFat mass index, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e12.44\u0026plusmn;4.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e12.61\u0026plusmn;5.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003ePercent body fat (%),mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e39.30\u0026plusmn;7.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e39.20\u0026plusmn;8.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003e\u003cem\u003eBreast tumor characteristics\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eTumor grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eWell differentiated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e107 (16.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e13 (9.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eModerately differentiated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e219 (34.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e45 (31.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003ePoorly differentiated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e309 (48.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e86 (59.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eTumor size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003e\u0026lt;1.0 cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e149 (20.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e22 (14.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003e1.0-2.0 cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e281 (38.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e64 (43.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003e\u0026gt;2.0 cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e292 (40.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e62 (41.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eAJCC stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eStage 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e62 (8.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e1 (0.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eStage I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e257 (37.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e54 (39.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eStage II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e271 (39.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e66 (47.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eStage III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e96 (13.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e14 (10.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eStage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e6 (0.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e3 (2.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eER status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eER+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e505 (70.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e84 (56.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eER-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e215 (29.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e64 (43.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eHER2 status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eHER2-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e412 (81.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e112 (75.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.34615384615385%\"\u003e\n \u003cp\u003eHER2+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.608974358974358%\"\u003e\n \u003cp\u003e93 (18.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.044871794871796%\"\u003e\n \u003cp\u003e36 (24.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e In the protein expression sample, age was missing for 22 (3%); BMI was missing for 23 (3.2%); waist circumference, hip circumference, and waist-to-hip ratio were missing for 33 (4.6%); fat mass index was missing for 66 (9.1%); percent body fat was missing for 64 (8.9%); tumor grade was missing for 87 (12%); tumor stage was missing for 30 (4.2%); ER status was missing for 2 (0.3%), and HER2 status was missing for 18 (2.5%) participants.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e In the gene expression sample, age, menopausal status, race, and BMI was missing for 4 (2.7%) participants; waist circumference, hip circumference, and waist-to-hip ratio were missing for 5 (3.4%) participants; fat mass index and percent body fat were missing for 12 (8.1%) participants; tumor grade was missing for 4 (2.7%) participants; and tumor stage was missing for 10 (6.8%) participants.\u003c/p\u003e\n\u003cp\u003eThere was a weak positive correlation between LEPR protein and \u003cem\u003eLEPR\u003c/em\u003e gene expression (r = 0.29, P = 0.0006), no significant correlation between ADIPOR1 protein and \u003cem\u003eADIPOR1\u003c/em\u003e gene expression (r = -0.03, P = 0.69), and a very weak positive correlation between ADIPOR2 protein and ADIPOR2 gene expression (r = 0.18, P = 0.04). In models adjusting for race, menopausal status, and ER status, we found that women with greater body fatness had significantly higher LEPR protein expression: BMI (b = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (b = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (b = 0.0015, 95% CI: 0.0007, 0.0024), and fat mass index (b = 0.0041, 95% CI: 0.0015, 0.0067) (\u003cstrong\u003eTable 2\u003c/strong\u003e). These findings, which were significant with correction for multiple comparisons, equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for each standard deviation increase in BMI, waist circumference, hip circumference, and fat mass index, respectively. WHR was not associated with LEPR protein expression. Upon further adjustment for waist circumference, the observed associations between BMI (P = 0.08), hip circumference (P = 0.13), and percent body fat (P = 0.26) were consistent but attenuated, while the association for fat mass index was slightly stronger (b = 0.0055, 95% CI: 0.0005, 0.0010; 24.1% increase in LEPR protein expression), although not statistically significant (data not shown). Conversely, we found no association between body fatness and \u003cem\u003eLEPR\u0026nbsp;\u003c/em\u003egene expression. Associations between body fatness and ADIPOR1 expression (\u003cstrong\u003eTable 3\u003c/strong\u003e) and ADIPOR2 expression (\u003cstrong\u003eTable 4\u003c/strong\u003e) were also not statistically significant, but the coefficients suggested that increasing body fatness might be associated with lower protein expression and higher gene expression.\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eMultivariable-adjusted associations of body fatness measures with LEPR protein and LEPR gene expression in breast tumor tissues.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"19.312169312169313%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" width=\"40.74074074074074%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLEPR protein expression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" width=\"39.94708994708995%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eLEPR\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;gene expression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.913256955810148%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta; (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.456628477905074%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003estandardized\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.819967266775777%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.567921440261866%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta; (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.456628477905074%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003estandardized\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01963993453355%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.28665785997358%\"\u003e\n \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e571\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.494055482166445%\"\u003e\n \u003cp\u003e0.0028 (0.0011, 0.0045)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.926023778071334%\"\u003e\n \u003cp\u003e0.002**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.022457067371203%\"\u003e\n \u003cp\u003e0.0062 (-0.0187, 0.0312)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.472919418758257%\"\u003e\n \u003cp\u003e0.625\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.28665785997358%\"\u003e\n \u003cp\u003eWaist circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e561\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.494055482166445%\"\u003e\n \u003cp\u003e0.0013 (0.0005, 0.0022)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.926023778071334%\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.022457067371203%\"\u003e\n \u003cp\u003e-0.0003 (-0.0122, 0.0116)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e-0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.472919418758257%\"\u003e\n \u003cp\u003e0.962\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.28665785997358%\"\u003e\n \u003cp\u003eHip circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e561\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.494055482166445%\"\u003e\n \u003cp\u003e0.0015 (0.0007, 0.0024)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.926023778071334%\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.022457067371203%\"\u003e\n \u003cp\u003e-0.0006 (-0.0134, 0.0122)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e-0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.472919418758257%\"\u003e\n \u003cp\u003e0.927\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.28665785997358%\"\u003e\n \u003cp\u003eWaist-to-hip ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e561\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.494055482166445%\"\u003e\n \u003cp\u003e0.0537 (-0.1131, 0.2206)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.926023778071334%\"\u003e\n \u003cp\u003e0.528\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.022457067371203%\"\u003e\n \u003cp\u003e-0.1725 (-2.8365, 2.4914)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e-0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.472919418758257%\"\u003e\n \u003cp\u003e0.899\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.28665785997358%\"\u003e\n \u003cp\u003eFat mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e534\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.494055482166445%\"\u003e\n \u003cp\u003e0.0041 (0.0015, 0.0067)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.926023778071334%\"\u003e\n \u003cp\u003e0.002**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.022457067371203%\"\u003e\n \u003cp\u003e0.0091 (-0.0275, 0.0458)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.472919418758257%\"\u003e\n \u003cp\u003e0.626\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.28665785997358%\"\u003e\n \u003cp\u003ePercent body fat (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e536\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.494055482166445%\"\u003e\n \u003cp\u003e0.0020 (0.0004, 0.0036)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.926023778071334%\"\u003e\n \u003cp\u003e0.016*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1519154557463676%\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.022457067371203%\"\u003e\n \u003cp\u003e-0.0012 (-0.0246, 0.0228)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.247027741083222%\"\u003e\n \u003cp\u003e-0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.472919418758257%\"\u003e\n \u003cp\u003e0.941\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eNOTE: Protein expression scores reflect quantitative protein expression (using immunohistochemistry) of LEPR as analyzed through an automated/unsupervised scoring (quantitative) methodology. The scores estimate the effective staining intensity (ESI) within the effective staining area (ESA) of the biomarker in question (mean\u0026plusmn;SD of log-transformed values are shown). Gene expression scores reflect normalized, log2-transformed gene expression of \u003cem\u003eLEPR\u003c/em\u003e as analyzed through the Nanostring nCounter Analysis System. Each model was generated using multiple linear regression adjusting for race, menopausal status, and estrogen receptor status.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e* Statistically significant at P\u0026lt;0.05; ** Statistically significant with correction for multiple comparisons (P \u0026lt;0.0083).\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" style=\"width: 43.6301%;\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eMultivariable-adjusted associations of body fatness measures with ADIPOR1 protein and \u003cem\u003eADIPOR1\u003c/em\u003e gene expression in breast tumor tissues.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8.3489%;\" width=\"20.32085561497326%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 20.5999%;\" width=\"40.106951871657756%\"\u003e\n \u003cp\u003e\u003cstrong\u003eADIPOR1 protein expression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 14.4091%;\" width=\"39.43850267379679%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eADIPOR1\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003egene expression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 2.5863%;\" width=\"6.375838926174497%\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.5286%;\" width=\"24.161073825503355%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta; (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1273%;\" width=\"11.74496644295302%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003estandardized\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.3577%;\" width=\"8.053691275167786%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.6317%;\" width=\"6.543624161073826%\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.0295%;\" width=\"23.48993288590604%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta; (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.8114%;\" width=\"11.74496644295302%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003estandardized\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1.6789%;\" width=\"7.382550335570469%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.3489%;\" width=\"20.32085561497326%\"\u003e\n \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.5863%;\" width=\"5.080213903743315%\"\u003e\n \u003cp\u003e665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.5286%;\" width=\"19.25133689839572%\"\u003e\n \u003cp\u003e-0.0008 (-0.0028, 0.0013)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1273%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e-0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.3577%;\" width=\"6.4171122994652405%\"\u003e\n \u003cp\u003e0.473\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.6317%;\" width=\"5.213903743315508%\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.0295%;\" width=\"18.71657754010695%\"\u003e\n \u003cp\u003e0.0070 (-0.0045, 0.0184)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.8114%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e0.128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1.6789%;\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003e0.234\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.3489%;\" width=\"20.32085561497326%\"\u003e\n \u003cp\u003eWaist circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.5863%;\" width=\"5.080213903743315%\"\u003e\n \u003cp\u003e654\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.5286%;\" width=\"19.25133689839572%\"\u003e\n \u003cp\u003e-0.0002 (-0.0011, 0.0008)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1273%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e-0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.3577%;\" width=\"6.4171122994652405%\"\u003e\n \u003cp\u003e0.761\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.6317%;\" width=\"5.213903743315508%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.0295%;\" width=\"18.71657754010695%\"\u003e\n \u003cp\u003e0.0048 (-0.0007, 0.0102)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.8114%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1.6789%;\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.3489%;\" width=\"20.32085561497326%\"\u003e\n \u003cp\u003eHip circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.5863%;\" width=\"5.080213903743315%\"\u003e\n \u003cp\u003e654\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.5286%;\" width=\"19.25133689839572%\"\u003e\n \u003cp\u003e-0.0004 (-0.0014, 0.0007)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1273%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e-0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.3577%;\" width=\"6.4171122994652405%\"\u003e\n \u003cp\u003e0.497\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.6317%;\" width=\"5.213903743315508%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.0295%;\" width=\"18.71657754010695%\"\u003e\n \u003cp\u003e0.0032 (-0.0032, 0.0086)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.8114%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e0.091\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1.6789%;\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003e0.367\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.3489%;\" width=\"20.32085561497326%\"\u003e\n \u003cp\u003eWaist-to-hip ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.5863%;\" width=\"5.080213903743315%\"\u003e\n \u003cp\u003e654\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.5286%;\" width=\"19.25133689839572%\"\u003e\n \u003cp\u003e0.0474 (-0.1447, 0.2394)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1273%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.3577%;\" width=\"6.4171122994652405%\"\u003e\n \u003cp\u003e0.629\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.6317%;\" width=\"5.213903743315508%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.0295%;\" width=\"18.71657754010695%\"\u003e\n \u003cp\u003e1.1785 (-0.0507, 2.4078)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.8114%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e0.212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1.6789%;\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003e0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.3489%;\" width=\"20.32085561497326%\"\u003e\n \u003cp\u003eFat mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.5863%;\" width=\"5.080213903743315%\"\u003e\n \u003cp\u003e624\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.5286%;\" width=\"19.25133689839572%\"\u003e\n \u003cp\u003e-0.0019 (-0.0050, 0.0013)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1273%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e-0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.3577%;\" width=\"6.4171122994652405%\"\u003e\n \u003cp\u003e0.249\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.6317%;\" width=\"5.213903743315508%\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.0295%;\" width=\"18.71657754010695%\"\u003e\n \u003cp\u003e0.0081 (-0.0091, 0.0252)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.8114%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e0.104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1.6789%;\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003e0.357\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 8.3489%;\" width=\"20.32085561497326%\"\u003e\n \u003cp\u003ePercent body fat (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.5863%;\" width=\"5.080213903743315%\"\u003e\n \u003cp\u003e626\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.5286%;\" width=\"19.25133689839572%\"\u003e\n \u003cp\u003e-0.0016 (-0.0036, 0.0003)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1273%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e-0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.3577%;\" width=\"6.4171122994652405%\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2.6317%;\" width=\"5.213903743315508%\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.0295%;\" width=\"18.71657754010695%\"\u003e\n \u003cp\u003e0.0045 (-0.0066, 0.0156)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 3.8114%;\" width=\"9.358288770053475%\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1.6789%;\" width=\"5.882352941176471%\"\u003e\n \u003cp\u003e0.424\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eNOTE: Protein expression scores reflect quantitative protein expression (using immunohistochemistry) of ADIPOR1 as analyzed through an automated/unsupervised scoring (quantitative) methodology. The scores estimate the effective staining intensity (ESI) within the effective staining area (ESA) of the biomarker in question (mean\u0026plusmn;SD of log-transformed values are shown). Gene expression scores reflect normalized, log2-transformed gene expression of \u003cem\u003eADIPOR1\u003c/em\u003e as analyzed through the Nanostring nCounter Analysis System. Each model was generated using multiple linear regression adjusting for race, menopausal status, and estrogen receptor status.\u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"9\" width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003eMultivariable-adjusted associations of body fatness measures with ADIPOR2 protein and \u003cem\u003eADIPOR2\u003c/em\u003e gene expression in breast tumor tissues.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"19.466666666666665%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" width=\"40%\"\u003e\n \u003cp\u003e\u003cstrong\u003eADIPOR2 protein expression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" width=\"40.53333333333333%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eADIPOR2\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003egene expression\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.435643564356436%\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.762376237623762%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta; (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.551155115511552%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003estandardized\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.920792079207921%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.260726072607261%\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.102310231023104%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta; (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.551155115511552%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003estandardized\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.415841584158416%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.414893617021278%\"\u003e\n \u003cp\u003eBody mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1861702127659575%\"\u003e\n \u003cp\u003e584\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.148936170212767%\"\u003e\n \u003cp\u003e-0.0003 (-0.0028, 0.0023)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e-0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e0.844\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.851063829787234%\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.617021276595743%\"\u003e\n \u003cp\u003e0.0098 (-0.0103, 0.0300)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.781914893617022%\"\u003e\n \u003cp\u003e0.346\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.414893617021278%\"\u003e\n \u003cp\u003eWaist circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1861702127659575%\"\u003e\n \u003cp\u003e575\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.148936170212767%\"\u003e\n \u003cp\u003e-0.0003 (-0.0015, 0.0009)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e-0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e0.585\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.851063829787234%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.617021276595743%\"\u003e\n \u003cp\u003e0.0085 (-0.0012, 0.0182)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.182\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.781914893617022%\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.414893617021278%\"\u003e\n \u003cp\u003eHip circumference (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1861702127659575%\"\u003e\n \u003cp\u003e575\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.148936170212767%\"\u003e\n \u003cp\u003e-0.0001 (-0.0014, 0.0012)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e-0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e0.873\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.851063829787234%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.617021276595743%\"\u003e\n \u003cp\u003e0.0046 (-0.0058, 0.0150)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.087\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.781914893617022%\"\u003e\n \u003cp\u003e0.387\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.414893617021278%\"\u003e\n \u003cp\u003eWaist-to-hip ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1861702127659575%\"\u003e\n \u003cp\u003e575\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.148936170212767%\"\u003e\n \u003cp\u003e-0.0389 (-0.2773, 0.1995)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e-0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e0.749\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.851063829787234%\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.617021276595743%\"\u003e\n \u003cp\u003e2.1901 (0.0181, 4.3621)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.781914893617022%\"\u003e\n \u003cp\u003e0.050\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.414893617021278%\"\u003e\n \u003cp\u003eFat mass index (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1861702127659575%\"\u003e\n \u003cp\u003e552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.148936170212767%\"\u003e\n \u003cp\u003e0.0002 (-0.0037, 0.0040)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e0.939\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.851063829787234%\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.617021276595743%\"\u003e\n \u003cp\u003e0.0155 (-0.0146, 0.0456)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.781914893617022%\"\u003e\n \u003cp\u003e0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.414893617021278%\"\u003e\n \u003cp\u003ePercent body fat (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.1861702127659575%\"\u003e\n \u003cp\u003e554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.148936170212767%\"\u003e\n \u003cp\u003e0.0007 (-0.0017, 0.0031)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.382978723404255%\"\u003e\n \u003cp\u003e0.557\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.851063829787234%\"\u003e\n \u003cp\u003e136\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.617021276595743%\"\u003e\n \u003cp\u003e0.0136 (-0.0058, 0.0330)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.308510638297872%\"\u003e\n \u003cp\u003e0.151\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.781914893617022%\"\u003e\n \u003cp\u003e0.171\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eNOTE: Protein expression scores reflect quantitative protein expression (using immunohistochemistry) of ADIPOR2 as analyzed through an automated/unsupervised scoring (quantitative) methodology. The scores estimate the effective staining intensity (ESI) within the effective staining area (ESA) of the biomarker in question (mean\u0026plusmn;SD of log-transformed values are shown). Gene expression scores reflect normalized, log2-transformed gene expression of \u003cem\u003eADIPOR2\u003c/em\u003e as analyzed through the Nanostring nCounter Analysis System. Each model was generated using multiple linear regression adjusting for race, menopausal status, and estrogen receptor status.\u003c/p\u003e\n\u003cp\u003eGiven the multivariable-adjusted associations observed between measures of body fatness and LEPR protein expression levels, we explored potential differences by race (\u003cstrong\u003eTable S1\u003c/strong\u003e), menopausal status (\u003cstrong\u003eTable S2\u003c/strong\u003e), and ER status (\u003cstrong\u003eTable S3\u003c/strong\u003e). Qualitatively, our observation that increasing body fatness measures are associated with higher LEPR protein expression appeared stronger among White women, postmenopausal women, and ER+ cases. Formal tests of interaction yielded statistically significant evidence of effect modification by race for some body fatness measures (BMI, P = 0.041; fat mass index, P = 0.016; and percent body fat, P = 0.019), but not others (waist circumference, P = 0.080; hip circumference, P = 0.086) (data not shown). However, we observed no evidence of effect modification by menopausal status (P-values for all body fatness measures \u0026gt;0.05), and limited evidence of effect modification by ER status (BMI, P = 0.318; waist circumference, P = 0.093; hip circumference, P = 0.059; WHR, P = 0.821; fat mass index, P = 0.250; and percent body fat, P = 0.553) (data not shown).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBuilding on our prior research, here we examined the association of body fatness measures with protein and gene expression of the adipokine receptors, LEPR, ADIPOR1, and ADIPOR2 in the breast tumor microenvironment. To our knowledge, this is the first study to investigate these associations in women with breast cancer. Partially consistent with our hypothesis, greater body fatness is associated with increased LEPR protein expression, although we observed no association between body fatness and \u003cem\u003eLEPR\u003c/em\u003e gene expression, nor with protein or gene expression of ADIPOR1 and ADIPOR2.\u003c/p\u003e \u003cp\u003ePast studies show that BMI is positively associated with circulating leptin concentrations and inversely associated with circulating adipokine concentrations, which are associated with increased risk of some obesity-related cancers including breast cancer (reviewed by Yoon et al (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e)). Our findings that increasing measures of body fatness are positively associated with LEPR protein expression in breast tumors independent of age and menopausal status (with correction for multiplicity) support the hypothesis that LEPR protein expression in breast tumor tissues play a role in breast carcinogenesis (\u003cspan additionalcitationids=\"CR50 CR51 CR52 CR53\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Interestingly, our analysis showed significant effect modification by race (stronger among White women) and marginally significant effect modification by ER status (suggestion of stronger associations among ER\u0026thinsp;+\u0026thinsp;cases, although our analysis was underpowered given the small sample of ER- cases). These findings further highlight the complex interplay among LEPR protein expression, adiposity, race, and breast tumor phenotype (\u003cspan additionalcitationids=\"CR56 CR57\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e), which might require more precise adiposity measures, and identification and refinement of adiposity-associated biomarkers within breast tumor tissues that can predict breast cancer outcomes. We observed no significant associations between body fatness and \u003cem\u003eLEPR\u003c/em\u003e gene expression, but we previously showed that gene expression of \u003cem\u003eLEPR\u003c/em\u003e is significantly lower in ER- and TN breast tumors relative to ER\u0026thinsp;+\u0026thinsp;and luminal A subtypes, respectively (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). While our sample with data on adipokine receptor gene expression was small and limited our statistical power, larger studies in the future will help clarify these findings. Nonetheless, our findings suggest that distribution of adiposity and adiposity-related expression profiles of LEPR, ADIPOR1, and ADIPOR2 in the local organ might have differential impacts on breast cancer based on tumor subtype, and the crosstalk between ER and adipokine biomarkers and other inflammatory biomarkers might play a role (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrior analysis from WCHS reported a lack of association between BMI and breast cancer risk, but higher hip circumference and waist circumference were associated with more than 2-fold increased risk of pre-menopausal breast cancer among women in the fourth quartiles for each measure compared to the first quartile.\u003csup\u003e42\u003c/sup\u003e Further, findings from WCHS also showed that compared to BMI, WHR had a stronger association with overall and breast cancer-specific mortality among Black women. Specifically, compared to the first quartile, women in the fourth quartile of WHR had 61% and 68% increased risk of overall and breast cancer specific death, respectively, while women with class I and class II obesity (compared to normal weight) had statistically non-significant increased risk of death ranging from 17\u0026mdash;33% (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). From the combination of these findings, investigations of the associations between more accurate measures of adiposity and distribution (including overall adiposity, visceral adiposity, and subcutaneous adiposity assessed through computed tomography [CT]), in association with adipokine receptor protein and gene expression are critical to elucidating the impact of adiposity on breast carcinogenesis and progression.\u003c/p\u003e \u003cp\u003eAn important strength of this study is that it adds to knowledge regarding the potential impact of overall and central body fatness on adiposity-related biomarkers in breast tumor tissues. Our findings suggest that measures of body fatness are associated with the expression of adipokine receptors \u0026ndash; primarily LEPR \u0026ndash; in breast tumors. From this, we generated new hypotheses about the mechanisms linking central adiposity with breast cancer outcomes, which will be pursued. Another strength was the opportunity to perform stratified analysis of the associations of interest by ER status, yielding novel findings. Lastly, was our population-based sample that included a large proportion of Black women with breast cancer was also a strength. This study also has some limitations worth noting, including a relatively small sample size (particularly in the gene expression analysis [n\u0026thinsp;=\u0026thinsp;148]), which may have reduced the power to detect meaningful associations and limit our ability to fully evaluate the complex associations of body fatness and breast cancer. Relatedly, our analysis included multiple comparisons which may have increased the likelihood of observing statistically significant associations. However, we addressed this concern using Bonferroni correction.\u003c/p\u003e \u003cp\u003eDespite these limitations, the findings substantiated our hypothesis that measures of body fatness are associated with protein expression of the adipokine receptors (namely, LEPR) in the breast tumor microenvironment. These data are an important step towards understanding the biologic effects of and potential mechanisms linking adiposity with breast cancer risk and prognosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADIPOQ: adiponectin\u003c/p\u003e\n\u003cp\u003eADIPOR1: adiponectin receptor 1\u003c/p\u003e\n\u003cp\u003eADIPOR2: adiponectin receptor 2\u003c/p\u003e\n\u003cp\u003eBIA: bioelectrical impedance analysis\u003c/p\u003e\n\u003cp\u003eBMI: body mass index\u003c/p\u003e\n\u003cp\u003eCI: confidence interval\u003c/p\u003e\n\u003cp\u003eCT: computed tomography\u003c/p\u003e\n\u003cp\u003eDCIS: ductal carcinoma in situ\u003c/p\u003e\n\u003cp\u003eER: estrogen receptor\u003c/p\u003e\n\u003cp\u003eESA: effective staining area\u003c/p\u003e\n\u003cp\u003eESI: effective staining intensity\u003c/p\u003e\n\u003cp\u003eFFPE:\u0026nbsp;formalin-fixed paraffin-embedded\u003c/p\u003e\n\u003cp\u003eH\u0026amp;E:\u0026nbsp;hematoxylin and eosin\u003c/p\u003e\n\u003cp\u003eHER2:\u0026nbsp;human epidermal growth factor receptor 2\u003c/p\u003e\n\u003cp\u003eLEPR: leptin receptor\u003c/p\u003e\n\u003cp\u003eSD: standard deviation\u003c/p\u003e\n\u003cp\u003eTMA: tissue microarray\u003c/p\u003e\n\u003cp\u003eTMA-AID:\u003c/p\u003e\n\u003cp\u003eTN: triple negative\u003c/p\u003e\n\u003cp\u003eWCHS: Women\u0026rsquo;s Circle of Health Study\u003c/p\u003e\n\u003cp\u003eWHR: waist-to-hip ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received ethics approval from the Rutgers University Institutional Review Board. All study methods were carried out in accordance with the requirements of the United States Common Rule (45CFR 46, U.S. Department of Health \u0026amp; Human Services [HHS], Office for Human Research Protections [OHRP]). All study participants provided written informed consent prior to study enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by funding from the National Cancer Institute of the National Institutes of Health under the following award numbers: K01CA193527 (awarded to A.A.M. Llanos), P01CA151135 (awarded to C.B. Ambrosone), P30CA072720 (awarded to S. Libutti), R01CA100598 (awarded to C.B. Ambrosone), R01CA185623 (awarded to E.V. Bandera, K. Demissie, and C.C. Hong), K08CA172722 (awarded to C. Omene), K07CA201334 (awarded to T-Y.D. Cheng), and K01CA226155 (awarded to EMC. Feliciano). Support was also received by the U.S. Army Medical Research and Development Command under award number DAMD‐17‐01‐1‐0334 (awarded to D.H. Bovbjerg), the Breast Cancer Research Foundation (awarded to C.B. Ambrosone and C.C. Hong), and a gift from the Philip L. Hubbell Family (awarded to C.B. Ambrosone). Tumor samples were received, processed and tracked under the auspices of the Roswell Park Comprehensive Cancer Center Data Bank and BioRepository Shared Resource, with funding from NCI-CCSG P30CA16056. Services, results and/or products in support of this research project were generated using the Rutgers Cancer Institute of New Jersey Biomedical Informatics Shared Resource (P30CA072720-5917) and the Biospecimen Repository and Histopathology Service Shared Resource (P30CA072720-5919). The New Jersey State Cancer Registry is funded by the National Cancer Institute\u0026rsquo;s Surveillance, Epidemiology and End Results (SEER) Program (#75N91021D00009), Centers for Disease Control and Prevention\u0026rsquo;s National Program of Cancer Registries (#5NU58DP006279) with additional support from the State of New Jersey and the Rutgers Cancer Institute of New Jersey.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAAML: grant funding, study conception and design, data collection, data analysis, data interpretation, and writing; JBA: literature search and data interpretation. TDC: data interpretation and manuscript editing; WC: data collection and manuscript editing. MAC: pathology review, data collection, and manuscript editing. EMCF: data interpretation and manuscript editing. BQ: data collection, data interpretation, and manuscript editing. YL: data analysis, data interpretation, and manuscript editing. CO: data interpretation and manuscript editing. TK: pathology review, data collection, and manuscript editing. CH: grant funding, data collection, and manuscript editing. SY: data collection, data interpretation, and manuscript editing. CBA: grant funding, data collection, data interpretation, and manuscript editing. EVB: grant funding, data collection, data interpretation, and manuscript editing. KD: grant funding, data collection, data interpretation, and manuscript editing. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are sincerely appreciative of the breast cancer advocates, community partners, and all study participants who made this work possible. We are equally grateful to the highly motivated, hardworking research personnel of the Women\u0026rsquo;s Circle of Health Study at the Rutgers School of Public Health, Rutgers Cancer Institute of New Jersey, Roswell Park Comprehensive Cancer Center, Mount Sinai School of Medicine (now Icahn School of Medicine at Mount Sinai), and the New Jersey State Cancer Registry.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePearson-Stuttard J, Zhou B, Kontis V, Bentham J, Gunter MJ, Ezzati M. Worldwide burden of cancer attributable to diabetes and high body-mass index: a comparative risk assessment. 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Biochem Pharmacol. 2019;161:73\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolm JB, Rosendahl AH, Borgquist S. Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer. Cancers (Basel). 2021;13(24).\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":"adiposity, breast cancer, leptin receptor, adiponectin receptor 1, adiponectin receptor 2, protein expression, gene expression, breast tumor tissues","lastPublishedDoi":"10.21203/rs.3.rs-1374841/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1374841/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe molecular mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their respective receptors in the breast tumor microenvironment may play a role.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index, and percent body fat with protein expression (log-transformed, n\u0026thinsp;=\u0026thinsp;722) and gene expression (log2-transformed, n\u0026thinsp;=\u0026thinsp;148) of leptin receptor (LEPR) and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn multivariable models, we found that increasing BMI (β\u0026thinsp;=\u0026thinsp;0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β\u0026thinsp;=\u0026thinsp;0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β\u0026thinsp;=\u0026thinsp;0.0015, 95% CI: 0.0007, 0.0024), and fat mass index (β\u0026thinsp;=\u0026thinsp;0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These findings reflect a 16.8%, 17.6%, 17.7%, 17.2% increase in LEPR protein expression for each standard deviation increase in BMI, waist circumference, hip circumference, and fat mass index, respectively. These associations were stronger among White and postmenopausal women and ER\u0026thinsp;+\u0026thinsp;cases; formal tests of interaction yielded evidence of effect modification by race. We found no associations of any measure of body fatness with \u003cem\u003eLEPR\u003c/em\u003e gene expression or with gene or protein expression of ADIPOR1 and ADIPOR2.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThese findings support an association of increased body fatness \u0026ndash; beyond overall body size measured using BMI \u0026ndash; with higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step.\u003c/p\u003e","manuscriptTitle":"Greater Body Fatness is Associated with Higher Protein Expression of LEPR in Breast Tumor Tissues: Cross-Sectional Analysis in the Women’s Circle of Health Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-02-22 18:44:19","doi":"10.21203/rs.3.rs-1374841/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":"fe8a8e0b-e435-4055-b6b3-f1a88040fe75","owner":[],"postedDate":"February 22nd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-02-22T18:44:20+00:00","versionOfRecord":[],"versionCreatedAt":"2022-02-22 18:44:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1374841","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1374841","identity":"rs-1374841","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}