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

了解肿瘤微环境中肥胖和脂肪因子相关 RNA 表达对种族和民族多样化样本中乳腺癌结果的作用

• 批准号: 10602753
• 负责人: Elizabeth Marjorie Cespedes Feliciano
• 金额: $ 73.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602753
• 关键词: Adipose tissue; Asian; Asian Americans; Biological Markers; Black American; Black race; Body Composition; Body fat; Body mass index; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; California; Cancer Prognosis; Cells; Cessation of life; Complex; Computerized Medical Record; Data; Detection; Development; Diagnosis; Drug or chemical Tissue Distribution; ERBB2 gene; Ethnic Origin; Ethnic Population; Exhibits; Fatty acid glycerol esters; Female; Gene Expression; Genes; Genetic Transcription; Hip region structure; Hispanic; Hispanic Americans; In Situ Hybridization; Incidence; Inequity; Intervention; LEPR gene; Leptin; Link; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Measures; Modeling; Modification; Muscle; Nonmetastatic; Not Hispanic or Latino; Obesity; Outcome; Pacific Islander; Phenotype; Physiological; Precision therapeutics; Prevalence; Prognosis; RNA; Race; Receptor Gene; Recurrence; Recurrent Malignant Neoplasm; Research; Resources; Risk; Risk Reduction; Role; Sampling; Scanning; Skin; Specimen; Testing; Transcript; Tumor Markers; Tumor Subtype; Tumor Tissue; Variant; Visceral; Woman; X-Ray Computed Tomography; adipokines; adiponectin; black women; cancer recurrence; cancer risk; cell type; cohort; ethnic diversity; genetic signature; high body mass index; hormone receptor-negative; hormone receptor-positive; improved; indexing; individualized prevention; insight; leptin receptor; malignant breast neoplasm; mortality; novel; outcome prediction; predictive modeling; predictive signature; preventive intervention; programs; prospective; protein expression; racial difference; racial diversity; racial population; receptor; receptor expression; risk prediction; subcutaneous; transcriptome sequencing; transcriptomics; tumor; tumor microenvironment; waist circumference

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.

摘要 肥胖与乳腺癌的联系机制以及脂肪组织分布的变化如何起作用 乳腺癌复发率和死亡率的不平等仍有待确定。解开复杂的 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腺内肥胖相关生物标志物的鉴定和改进 可以预测乳腺癌预后的肿瘤组织。我们的初步研究表明， 内脏脂肪组织和皮下脂肪组织-通过计算机断层扫描（CT）评估-扫描 在预测癌症结果方面优于体重指数（BMI）。我们事先 研究还表明，脂肪因子、瘦素和脂联素的基因和蛋白表达， 受体在乳腺肿瘤组织中变化，通常，较低的表达与更具侵袭性的肿瘤相关。 特征（例如，更高级别、更大尺寸、激素受体阴性状态和三阴性亚型）。此外，本发明的目的是， 我们发现，增加身体肥胖的措施-一般肥胖（BMI），身体脂肪分布（腰围）， 腰围、臀围、腰臀比（WHR）和身体成分（脂肪质量指数、体脂百分比）-是 与乳腺肿瘤组织中更高的瘦素受体蛋白表达相关， 修改种族。在这些初步研究的基础上，我们假设脂肪组织库（内脏） vs.皮下）与脂肪因子和脂肪因子受体表达谱有不同的关联， 乳腺肿瘤微环境（TME）中的相关基因签名。应用多重RNA原位杂交技术 为了表征乳腺TME中脂肪因子和脂肪因子受体表达的丰度，CT扫描， 评估脂肪组织分布，并在1600人的大型多样化队列中进行RNA-seq转录组分析 对于患有乳腺癌的女性，我们将：（1）测试肥胖是否与细胞类型特异性RNA相关 乳腺肿瘤和邻近乳腺TME中瘦素、脂联素及其受体的表达谱;（2） 定义乳腺中瘦素、脂联素及其受体的RNA表达谱之间的关联 TME与肿瘤临床病理学;和（3）表征与瘦素相关的RNA表达谱， 脂联素及其受体在乳腺TME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腺TME中的基因表达谱产生新的见解 以及关于人种、种族和肿瘤亚型潜在差异的新信息。这些数据至关重要 对于将肿瘤标志物和系统因素整合到乳腺癌风险和结果预测模型中的努力， 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。