(PQA2) Reversing Carcinogenic Effect of Obesity on Basal-like Breast Cancer

描述(由申请人提供)：肥胖是基底细胞样乳腺癌(BBC)的既定危险因素，BBC是一种侵袭性的三重阴性亚型，对年轻的非裔美国女性影响不成比例。肥胖如何促进BBC仍不清楚，这引发了一个挑衅性的问题A2：肥胖如何导致癌症风险？这项提案的目的是通过利用BBC的小鼠模型来确定肥胖促进BBC的分子机制，从而解决这个挑衅性的问题。此外，该项目将评估肥胖的促肿瘤效应是否可逆，并将确定肝细胞生长因子(HGF)信号级联在这一过程中的作用。该项目建立在我们之前的数据基础上，该数据表明，在BBC的基因工程小鼠模型(GEMM)中，高脂饮食诱导的肥胖减少了肿瘤潜伏期，伴随着HGF分泌和cMET受体表达的变化。我们的假设是，肥胖对乳腺癌发生的影响可以通过饮食干预和/或药物手段通过依赖于HGF/cMET信号的机制来逆转。我们的目标是通过研究HGF/cMET信号在肥胖相关BBC潜伏期和进展中的作用，将流行病学观察与肥胖和BBC联系起来，并确定减少肥胖相关乳腺癌的可行策略。在目标1中，我们将评估这些表达变化是否可通过饮食调整(在高脂饮食诱导肥胖开始后转向低脂饮食)，并量化热量限制对正常乳腺和肿瘤潜伏期的影响。在目标2中，我们将针对高脂饮食诱导的肥胖动物的HGF/cMET途径进行药理学靶向，以评估其对潜伏期的影响。这两个目标都将利用已建立的模型系统，并将使用正常乳腺组织的基因和蛋白质表达分析来监测肥胖、饮食和HGF信号在BBC肿瘤产生的微环境中的分子影响。如果这些研究成功，这项研究将确定HGF/Met致癌信号是否在BBC病因学中发挥作用，从而为研究肥胖相关风险的遗传易感性开辟新的途径。通过饮食干预或药物疗法进行有针对性的干预将改变肥胖相关癌症预防领域，并可每年预防数千例乳腺癌。

DESCRIPTION (provided by applicant): Obesity is an established risk factor for basal-like breast cancer (BBC), an aggressive triple negative subtype that disproportionately affects young African American women. How obesity promotes BBC remains unknown, motivating provocative question A2: How does obesity contribute to cancer risk? The goal of this proposal is address this provocative question by utilizing mouse models of BBC to identify molecular mechanisms by which obesity promotes BBC. Furthermore, this project will evaluate whether the pro-tumorigenic effects of obesity are reversible and will establish the role of the hepatocyte growth factor (HGF) signaling cascade in this process. This project builds on our previous data demonstrating that high fat diet-induced obesity decreases tumor latency in a genetically engineered mouse model (GEMM) of BBC, concomitant with alterations in HGF secretion and cMET receptor expression. Our hypothesis is that obesity-induced effects on breast carcinogenesis can be reversed through dietary intervention and/or pharmacologic means via a mechanism that depends upon HGF/cMET signaling. We aim to link epidemiologic observations linking obesity and BBC with mechanistic underpinnings and to identify viable strategies for reducing obesity-associated breast cancer by studying the role of HGF/cMET signaling in obesity-associated BBC latency and progression. In Aim 1, we will evaluate whether these expression changes are reversible with dietary modification (cross over to a low fat diet after high fat diet-induced obesity onset) and we will quantify how caloric restriction affects the normal mammary gland and tumor latency. In Aim 2, we will pharmacologically target the HGF/cMET pathway in high fat diet-induced obese animals to evaluate the effect on latency. Both aims will take advantage of established model systems and will use gene and protein expression analysis of normal breast tissue to monitor the molecular effects of obesity, diet, and HGF signaling in the microenvironment from which BBC tumors arise. If these studies are successful, this research will establish whether HGF/Met oncogenic signaling plays a role in BBC etiology, leading to new avenues of research on genetic susceptibility to obesity-associated risk. Targeted intervention through dietary interventions or pharmacologic therapies would transform the field of obesity-associated cancer prevention and could prevent thousands of breast cancer each year.