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: 8633292
• 负责人: Gerald V Denis
• 金额: $ 60.6万
• 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/8633292
• 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）：尚不清楚肥胖和乳腺癌的免疫代谢并发症之间的机械关系，尤其是在非裔美国妇女中，这一群体受到不成比例的影响。胰岛素抵抗肥胖具有慢性全身性和局部炎症，与乳腺癌结局有关。但是，并非所有肥胖都传达出同样的癌症风险。尽管肥胖，大约四分之一的肥胖非裔美国人具有“代谢健康”，并且表现出降低的心血管和糖尿病风险。对弗雷明汉研究人群的数据的最新分析表明，这些受试者的肥胖相关癌症的风险也降低了。这些健康肥胖成年人的一个关键特征是炎症性降低，无论是在脂肪中还是全身性血液中。这些数据设定了我们的长期目标：了解和使用肥胖，炎症和乳腺癌结果之间的关系，以降低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在乳房组织中或系统地炎症是否较少，或者是免疫代谢状况是否有降低乳腺癌风险的伴侣。许多“代谢性”肥胖的非洲裔美国妇女被赋予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。批判性研究根本没有进行。鉴于美国人的数量受到了肥胖和癌症的影响，因此迫切需要解决这些问题。我们的方法将研究黑人妇女健康研究中的免疫代谢状况和乳腺癌，并使用基本实验室和流行病学人群数据来识别关键机制和药理解决方案。我们的总体目标是定义肥胖女性中癌症风险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，我们假设某些肥胖妇女的炎症减少了，可以预防乳腺癌。并且耐胰岛素肥胖的护理标准二甲双胍具有预防非洲乳腺癌的价值 美国妇女。该假设是根据Framingham和BWHS受试者的初步和发表的研究提出的。我们实现三个目标：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子。 2。确定炎症标志物，包括乳腺脂肪组织中的冠状结构和血浆细胞因子水平，与“代谢性无敏化”肥胖有关，而不是“代谢性健康”的肥胖症。 3。确定新型炎症和癌症的抑制剂是否会减少人类乳腺癌模型中的肿瘤细胞侵袭性。拟议的研究具有创新性和重要性，因为我们是第一个将肥胖症与乳腺癌风险相对的机制。调查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处境不利的人群的癌症死亡率。