Uncoupling obesity from breast cancer in African American women

非洲裔美国女性肥胖与乳腺癌的关系

• 批准号: 8740475
• 负责人: Gerald V Denis
• 金额: $ 58.86万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740475
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; African American; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Bacteriophages; Blood; Blood Glucose; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Caucasians; Caucasoid Race; Cell Culture Techniques; Chronic; Cross-Sectional Studies; Cytokine Signaling; Data; Data Set; Dental crowns; Disadvantaged; Epidemiology; Exhibits; Fatty acid glycerol esters; Goals; Health Status; Human; Individual; Inflammation; Inflammatory; Insulin Resistance; Intervention; Investigation; Laboratories; Link; Malignant Neoplasms; Mammary Gland Parenchyma; Measures; Medical; Metabolic; Metabolic syndrome; Metformin; Methods; Modeling; Morbid Obesity; Obesity; Obesity associated cancer; Outcome; Persons; Plasma; Population; Postmenopause; Prevalence; Production; Protein Inhibition; Public Health; Publishing; Relative (related person); Research; Risk; Solutions; Structure; Study Subject; Subgroup; Testing; Woman; Women' s Health; adverse outcome; base; cancer health disparity; cancer risk; cardiovascular risk factor; cohort; cytokine; diabetes risk; effective intervention; experience; glucose tolerance; high risk; improved; inflammatory marker; inhibitor/antagonist; innovation; malignant breast neoplasm; monocyte; mortality; neoplastic cell; novel; obesity risk; outcome forecast; population based; public health relevance; standard of care; tumor

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.

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，特别是在非洲裔美国女性中，这一群体受到的影响尤为严重。胰岛素抵抗性肥胖的特点是慢性全身和局部脂肪炎症，这与乳腺癌的结果有关。然而，并非所有肥胖都会带来相同的癌症风险。尽管肥胖，但大约四分之一的肥胖非洲裔美国成年人“代谢健康”，并且心血管和糖尿病风险降低。最近对弗雷明汉研究基于人群的数据的分析表明，这些受试者患肥胖相关癌症（包括乳腺癌）的风险也降低了。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特征减少。这些数据确立了我们的长期目标：了解并利用肥胖、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”的肥胖非洲裔美国女性的乳腺组织或全身炎症是否较少，或者免疫代谢状态是否与降低乳腺癌风险相关。许多“代谢异常”的肥胖非洲裔美国女性服用二甲双胍来控制血糖，但我们不知道二甲双胍是否可以保护她们免受乳腺癌的侵害；根本没有进行批判性研究。鉴于受影响的美国人数量以及肥胖和癌症造成的高死亡率，迫切需要解决这些问题。我们的方法将调查黑人妇女健康研究中的免疫代谢状态和乳腺癌，并使用基本实验室和流行病学人群数据来确定关键机制和药理学解决方案。我们的总体目标是定义对肥胖女性癌症风险进行分层的关键免疫代谢机制，并测试乳腺癌细胞培养模型中假设的关系。根据新的初步数据，我们假设减少某些肥胖女性的炎症可以预防乳腺癌；胰岛素抵抗性肥胖症的护理标准二甲双胍对于非洲乳腺癌的预防具有价值 美国妇女。该假设是根据 Framingham 和 BWHS 受试者的初步研究和已发表的研究制定的。我们的三个目标是： 1. 确定对 BWHS 受试者中与肥胖相关的乳腺癌风险进行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，而不是与“代谢健康”肥胖相关。 3. 确定新型炎症和癌症抑制剂是否可以降低人类乳腺癌模型中肿瘤细胞的侵袭性。拟议的研究具有创新性且重要，因为我们是第一个解开肥胖与乳腺癌风险相关机制的人。这项调查将对公共健康产生重要影响，因为我们的结果将有助于降低弱势群体的癌症死亡率。