Full Project 1: LSR Alters Metabolic Signaling to Drive Aggressive Breast Cancer Behaviors

项目摘要/摘要 与其他种族相比，非裔美国人(AA)女性的乳腺癌死亡率更高。一个更伟大的 再生障碍性贫血妇女中基底细胞样乳腺癌的流行解释了一些差异，因为这些肿瘤 临床上最具侵袭性的，以癌症干细胞为特征没有有效的治疗方法 单元格功能。 生存能力很差。加剧这种差距的是肥胖症的促病作用，这一点非常明显 再生障碍性贫血较高。大多数关于乳腺癌差异的研究都是研究肿瘤的特征，但 导致这种差异的病因仍未确定。我们的主要目标是确定 作为间质效应的结果，AAS促进侵袭性乳腺癌的机制 癌变的部位。已经确定了一条关键的分子途径，它整合了这些 影响肿瘤行为的临床、微环境和生物学因素。目标1采用了一种新的方法， 结合我们已发表的详细描述RACE和肿瘤亚型的蛋白质组和基因表达数据集 间质相互作用与我们最近发表的关于促进癌症干细胞的已识别途径的数据- 比如，攻击性行为。目标2和目标3将这些数据扩展到实验研究，以阐明机理 细节。为了完成这些任务，我们的团队建立了研究伙伴关系，提供了访问 包括正常乳房研究在内的资源：一项来自不同种族患者的独特流行病学研究 在北卡罗来纳大学医院。这项工作有几个重要的生物学意义。据观察，AA 乳房组织富含不同的蛋白质，AA肥胖症的患病率，以及 发生基底细胞样瘤强烈表明种族、新陈代谢和癌症亚型之间存在生物学联系。 差异调节的代谢敏感蛋白在肿瘤微环境中的作用将提供 对种族差异的生物学基础的新见解。我们合作的长期目标是 了解肿瘤与微环境的相互作用及其对乳腺癌差异的影响。我们的 独特的方法将揭示乳腺组织微环境的独特特征，并将 将肿瘤微环境领域的进展与健康差异研究相结合。 相关性 这项建议通过研究驱动侵袭性的关键途径来解决乳腺癌的差异。 乳腺癌的风险。通过结合对这一途径中种族、BMI和 乳腺癌亚型通过实验研究了解这一途径在细胞中的作用 从表型来看，这一项目将对种族差异的生物学基础提供重要而新颖的见解。

Project Summary/Abstract African American (AA) women have higher breast cancer mortality rates compared to other races. A greater prevalence of basal-like breast cancers in AA women explain some disparities, as these tumors are clinically the most aggressive, characterized by cancer stem No effective therapies exist and cell features. survival is poor. Escalating this disparity is the disease promoting effects of obesity, which is significantly higher in AA. The majority of studies on breast cancer disparities examine tumor characteristics, but the etiologic factors that lead to this disparity remain undefined. Our primary objective is to identify the mechanisms involved in promoting aggressive breast cancer in AAs, as a consequence of stromal effects at the site of the cancerous lesion. A key molecular pathway has been identified which integrates these clinical, microenvironmental and biological factors to affect tumor behavior. Aim 1 takes a novel approach, combining our published proteomic and gene expression datasets detailing race and tumor-subtype specific stromal interactions with our recently published data on the identified pathway promoting cancer stem cell- like, aggressive behaviors. Aims 2 and 3 extend these data to experimental studies to elucidate mechanistic details. To accomplish these tasks, our team established research partnerships that provides access to resources including the Normal Breast Study: a unique epidemiologic study from ethnically diverse patients at UNC Hospitals. There are several important biological implications of this work. The observation that AA breast tissue is enriched with distinct proteins, the prevalence of obesity in AA, and the predisposition to develop basal-like tumors strongly suggests a biological link between race, metabolism and cancer subtype. The role of differentially regulated metabolic-sensitive proteins in the tumor microenvironment will provide novel insights into the biological basis of racial disparities. The long-term goal of our collaboration is to understand tumor-microenvironment interactions and their influence on breast cancer disparities. Our distinctive approach will expose unique characteristics of the breast tissue microenvironment and will integrate advances in the field of tumor microenvironment with health disparities research. Relevance This proposal addresses breast cancer disparities by studying a key pathway that drive the aggressiveness of breast cancers. By combining observational studies on differences in this pathway by race, BMI, and breast cancer subtype with experimental studies to understand the role of this pathway in cellular phenotypes, this project will provide important and novel insight into the biological basis of racial disparities.