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

(PQA2) 逆转肥胖对基底样乳腺癌的致癌作用

• 批准号: 8590946
• 负责人: Liza Makowski-Hayes
• 金额: $ 19.24万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-07 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590946
• 关键词: Address; Adult; Affect; African American; Animals; Biochemistry; Biological Markers; Biological Models; Breast; Breast Cancer Risk Factor; Caloric Restriction; Cancer Etiology; Data; Development; Diet; Diet Modification; Dietary Intervention; Epidemiologist; Epidemiology; Epithelial; Fat-Restricted Diet; Fatty acid glycerol esters; Gene Expression; Genetic Crossing Over; Genetic Predisposition to Disease; Genetically Engineered Mouse; Goals; Hepatocyte Growth Factor; Intervention; Link; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Modeling; Molecular; Monitor; Normal tissue morphology; Obesity; Obesity associated cancer; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Play; Population; Predisposition; Prevention; Prevention strategy; Process; Public Health; Research; Research Personnel; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Time; Woman; base; cancer genomics; cancer prevention; cancer risk; carcinogenesis; early life exposure; early onset; epidemiologic data; inhibitor/antagonist; malignant breast neoplasm; meetings; metabolomics; modifiable risk; mortality; mouse model; obesity prevention; obesity risk; prevent; protein expression; public health relevance; receptor; receptor expression; tumor; tumor progression; tumorigenic

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.

描述（由申请人提供）：肥胖是基底样乳腺癌（BBC）的一个确定的危险因素，这是一种侵袭性三阴性亚型，对年轻的非裔美国女性影响很大。肥胖如何促进BBC仍然未知，这激发了一个具有争议性的问题A2：肥胖是如何增加癌症风险的？本提案的目标是通过利用小鼠BBC模型来确定肥胖促进BBC的分子机制来解决这个具有挑衅性的问题。此外，本项目将评估肥胖的致瘤作用是否可逆，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，证明高脂肪饮食诱导的肥胖在BBC基因工程小鼠模型（GEMM）中减少肿瘤潜伏期，同时改变HGF分泌和cMET受体表达。我们的假设是，肥胖对乳腺癌的影响可以通过饮食干预和/或药物手段通过依赖于HGF/cMET信号的机制逆转。我们的目标是将肥胖和BBC之间的流行病学观察与机制基础联系起来，并通过研究HGF/cMET信号在肥胖相关BBC潜伏期和进展中的作用，确定减少肥胖相关乳腺癌的可行策略。在目的1中，我们将评估这些表达变化是否可以通过饮食调整（在高脂肪饮食引起的肥胖发作后过渡到低脂肪饮食）逆转，我们将量化热量限制如何影响正常乳腺和肿瘤潜伏期。在Aim 2中，我们将在高脂肪饮食诱导的肥胖动物中以HGF/cMET途径为药理学靶点，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，并将利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效应。如果这些研究成功，本研究将确定HGF/Met致癌信号是否在BBC病因学中发挥作用，从而为肥胖相关风险的遗传易感性研究开辟新的途径。通过饮食干预或药物治疗的针对性干预将改变肥胖相关癌症预防领域，每年可以预防数千例乳腺癌。