Uncoupling obesity from breast cancer in African American women

描述（由申请人提供）：肥胖和乳腺癌的免疫代谢并发症之间的机制关系尚不清楚，特别是在非裔美国妇女中，这是一个不成比例的影响。胰岛素抵抗性肥胖的特征是脂肪的慢性全身性和局部炎症，这与乳腺癌的结果有关。然而，并不是所有的肥胖都具有相同的癌症风险。大约四分之一的肥胖非洲裔美国成年人尽管肥胖，但“代谢健康”，心血管和糖尿病风险降低。最近对Frachial Study人群数据的分析表明，肥胖相关癌症（包括乳腺癌）的风险在这些受试者中也有所降低。这些健康肥胖成年人的一个关键特征是局部脂肪和全身血液中的炎症减少。这些数据确立了我们的长期目标：了解和利用肥胖、炎症和乳腺癌结果之间的关系，以减少肥胖对癌症死亡率的影响。我们不知道“代谢健康”的肥胖非洲裔美国妇女是否在乳腺组织或全身炎症较少，或者免疫代谢状态是否与乳腺癌风险降低有关。许多“代谢异常”的肥胖非裔美国妇女服用二甲双胍来控制血糖，但我们不知道二甲双胍是否能保护她们免受乳腺癌的侵害;关键的研究根本没有进行。考虑到受影响的美国人数量以及肥胖和癌症引起的高死亡率，解决这些问题迫在眉睫。我们的方法将在黑人妇女健康研究中调查免疫代谢状态和乳腺癌，并使用基本的实验室和流行病学人口数据来确定关键机制和药理学解决方案。我们的总体目标是确定关键的免疫代谢机制，分层肥胖妇女的癌症风险，并测试乳腺癌细胞培养模型中假设的关系。基于新的初步数据，我们假设某些肥胖女性的炎症减少可以预防乳腺癌;胰岛素抵抗性肥胖的标准治疗二甲双胍对预防非洲女性乳腺癌有价值。 美国女人该假设是制定的基础上，初步和已发表的研究FRAWER和BWHS科目。我们有三个目标：1。确定BWHS受试者中与肥胖相关的乳腺癌风险分层的免疫代谢因素。2.确定炎症标志物，包括乳房脂肪组织中的冠状结构和血浆细胞因子水平，是否与“代谢异常”肥胖相关，而不是“代谢健康”肥胖。3.确定新型炎症和癌症抑制剂是否能降低人类乳腺癌模型中肿瘤细胞的侵袭性。这项研究具有创新性和重要性，因为我们是第一个解开肥胖与乳腺癌风险之间联系的机制。这项研究将对公共卫生产生重要影响，因为我们的结果将有助于降低弱势群体的癌症死亡率。

DESCRIPTION (provided by applicant): The mechanistic relationship between immunometabolic complications of obesity and breast cancer is not understood, particularly in African American women, a group that is disproportionately affected. Insulin- resistant obesity features chronic systemic and local inflammation of fat, which has been linked to breast cancer outcomes. However, not all obesity conveys the same risk of cancer. About a quarter of obese African American adults are 'metabolically-healthy' despite their obesity and show reduced cardiovascular and diabetes risks. Recent analyses of Framingham Study population-based data show that risks for obesity- associated cancers, including breast cancer, are also reduced in these subjects. A key feature of these healthy obese adults is a reduced inflammatory profile, both locally in fat and systemically in blood. These data set up our long-term goal: to understand and use the relationships between obesity, inflammation and breast cancer outcomes to reduce the effects of obesity on cancer mortality. We do not know whether 'metabolically-healthy' obese African American women have less inflammation in breast tissue or systemically, or whether immunometabolic status associates with reduced breast cancer risk. Many 'metabolically-abnormal' obese African American women are given metformin to control blood glucose, but we do not know if metformin protects them against breast cancer; the critical studies simply have not been performed. It is urgent to resolve these questions, given the numbers of Americans affected and the high mortality arising from obesity and cancer. Our approach will investigate immunometabolic status and breast cancer in the Black Women's Health Study and use both basic laboratory and epidemiological population data to identify critical mechanisms and pharmacological solutions. Our overall objective is to define the critical immunometabolic mechanisms that stratify cancer risk in obese women, and test hypothesized relationships in cell culture models of breast cancer. Based on new preliminary data, we hypothesize that reduced inflammation in certain obese women protects against breast cancer; and that the standard of care for insulin-resistant obesity, metformin, has value for prevention of breast cancer in African American women. The hypothesis is formulated on the basis of preliminary and published studies of Framingham and BWHS subjects. We undertake three Aims: 1. Determine the immunometabolic factors that stratify obesity-related risk of breast cancer in BWHS subjects. 2. Determine whether inflammatory markers, including crown-like structures in breast adipose tissue and plasma cytokine levels, are associated with 'metabolically-abnormal' obesity as opposed to 'metabolically-healthy' obesity. 3. Determine whether novel inhibitors of inflammation and cancer diminish tumor cell aggressiveness in models of human breast cancer. The proposed research is innovative and important because we are the first to disentangle mechanisms that couple obesity to breast cancer risk. The investigation will have important public health impact because our results will help reduce cancer mortality in a disadvantaged population.