Understanding the role of adiposity and adipokine-related RNA expression in the tumor microenvironment on breast cancer outcomes in a racially and ethnically diverse sample

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ABSTRACT The mechanisms linking adiposity with breast cancer and how variation in adipose tissue distribution contribute to inequities in breast cancer recurrence and mortality remain to be determined. Untangling the complex interactions among adiposity, race and ethnicity, and breast tumor phenotype is a first step, which requires precise adiposity measures and identification and refinement of adiposity-associated biomarkers within breast tumor tissues that can predict breast cancer outcomes. Our preliminary research has shown that the distribution of visceral adipose tissue and subcutaneous adipose tissue – assessed by computed tomography (CT) – scans differ by race and ethnicity and outperforms body mass index (BMI) in predicting cancer outcomes. Our prior research also showed that gene and protein expression of the adipokines, leptin and adiponectin, and their receptors vary in breast tumor tissues and generally, lower expression is associated with more aggressive tumor features (e.g., higher grade, larger size, hormone receptor negative status, and triple-negative subtype). Further, we found that increased body fatness measures – general obesity (BMI), body fat distribution (waist circumference, hip circumference, WHR), and body composition (fat mass index, percent body fat) – are associated with higher leptin receptor protein expression in breast tumor tissues, with evidence of effect modification by race. Building on these preliminary studies, we hypothesize that adipose tissue depots (visceral vs. subcutaneous) have differing associations with adipokine and adipokine receptor expression profiles and related gene signatures in the breast tumor microenvironment (TME). Using multiplex RNA in situ hybridization to characterize the abundance of adipokine and adipokine receptor expression in the breast TME, CT scans to assess adipose tissue distribution, and RNA-seq for transcriptomic analysis in a large, diverse cohort of 1600 women with breast cancer, we will: (1) Test whether adiposity is associated with cell type-specific RNA expression profiles of leptin, adiponectin, and their receptors in breast tumors and the adjacent breast TME; (2) Define associations between RNA expression profiles of leptin, adiponectin, and their receptors in the breast TME with tumor clinicopathology; and (3) Characterize RNA expression profiles associated with leptin, adiponectin, and their receptors in the breast TME to predict breast cancer recurrence and mortality. This study will yield novel insights on how adipose tissue distribution impacts gene expression profiles in the breast TME and new information about potential differences by race and ethnicity and tumor subtype. Such data are critical for efforts to integrate tumor markers and systemic factors into breast cancer risk and outcome prediction models, and to informing the development of precision prevention interventions and precision therapeutics for diverse breast cancer patients.