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)：肥胖症的免疫代谢并发症和乳腺癌之间的机制关系尚不清楚，特别是在非裔美国妇女中，这是一个受影响不成比例的群体。胰岛素抵抗肥胖症的特点是脂肪的慢性全身和局部炎症，这与乳腺癌的预后有关。然而，并不是所有的肥胖都会带来同样的癌症风险。大约四分之一肥胖的非裔美国成年人尽管肥胖，但在代谢方面是健康的，并显示出降低了心血管和糖尿病的风险。最近对Framingham Study基于人群的数据的分析表明，这些受试者患肥胖症相关癌症(包括乳腺癌)的风险也降低了。这些健康的肥胖成年人的一个关键特征是炎症特征减少，无论是局部脂肪还是血液中的全身炎症。这些数据确立了我们的长期目标：了解和利用肥胖、炎症和乳腺癌预后之间的关系，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裔美国女性是否乳房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。许多代谢异常的非裔美国肥胖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能保护她们免受乳腺癌的侵袭；关键的研究根本没有进行。考虑到受影响的美国人的数量以及肥胖和癌症导致的高死亡率，解决这些问题是当务之急。我们的方法将在黑人妇女健康研究中调查免疫代谢状况和乳腺癌，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物解决方案。我们的总体目标是确定肥胖女性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的假设关系。根据新的初步数据，我们假设某些肥胖女性减少炎症可以预防乳腺癌；治疗胰岛素抵抗肥胖症的标准二甲双胍对非洲乳腺癌的预防有价值。 美国女性。该假说是基于对弗雷明翰和BWHS受试者的初步研究和已发表的研究而形成的。我们有三个目标：1.确定影响BWHS受试者肥胖相关乳腺癌风险的免疫代谢因素。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和代谢健康肥胖有关。3.在人类乳腺癌模型中，确定新的炎症和癌症抑制剂是否会降低肿瘤细胞的侵袭力。这项拟议的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关系的机制的人。这项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弱势群体的癌症死亡率。