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

摘要 肥胖症与乳腺癌的联系机制以及脂肪组织分布的差异如何起作用 乳腺癌复发和死亡率方面的不平等仍有待确定。解开情结 肥胖、种族和民族以及乳腺肿瘤表型之间的相互作用是第一步，这需要 精确的肥胖测量以及乳房内肥胖相关生物标记物的识别和提炼 可以预测乳腺癌预后的肿瘤组织。我们的初步研究表明，这种分布 内脏脂肪组织和皮下脂肪组织-由计算机断层扫描(CT)评估-扫描 不同的种族和民族，在预测癌症结果方面优于身体质量指数(BMI)。我们的前辈 研究还表明，脂肪因子、瘦素和脂联素的基因和蛋白表达以及它们的 乳腺肿瘤组织中的受体各不相同，一般来说，低表达与更具侵袭性的肿瘤有关。 特征(例如，级别更高、体型更大、激素受体阴性状态和三阴性亚型)。此外， 我们发现，增加体脂衡量标准--一般肥胖(BMI)、体脂分布(腰围 腰围、臀围)和身体成分(脂肪质量指数、体脂百分比)-是 与乳腺肿瘤组织中较高的瘦素受体蛋白表达有关，并有证据表明 因种族而改变。在这些初步研究的基础上，我们假设脂肪组织仓库(内脏 与皮下脂肪因子和脂肪因子受体表达谱有不同的相关性 乳腺肿瘤微环境(TME)中的相关基因特征。利用多重RNA原位杂交技术 为了研究脂肪因子和脂肪因子受体在乳腺TME中的丰富表达，CT扫描显示 在1600名不同的大型队列中评估脂肪组织分布和用于转录分析的rna-seq 乳腺癌女性患者，我们将：(1)测试肥胖是否与细胞类型特异性RNA有关 瘦素、脂联素及其受体在乳腺肿瘤及癌旁组织中的表达 明确乳房中瘦素、脂联素及其受体的RNA表达谱之间的关系 TME与肿瘤临床病理；以及(3)表征与瘦素相关的RNA表达谱， 脂联素及其受体在乳腺TME中预测乳腺癌复发和死亡率。本研究 将对脂肪组织分布如何影响乳房TME中的基因表达谱产生新的见解 以及关于种族、民族和肿瘤亚型潜在差异的新信息。这些数据是至关重要的 为了将肿瘤标记物和系统因素整合到乳腺癌风险和结果预测模型中， 并为各种疾病的精确预防干预和精确治疗的发展提供信息 乳腺癌患者。

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.