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: 9134718
• 负责人: Gerald V Denis
• 金额: $ 56.52万
• 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/9134718
• 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; Cd68; Cell Culture Techniques; Chronic; Cross-Sectional Studies; Cytokine Signaling; Data; Data Set; Dental crowns; Disadvantaged; Epidemiology; Exhibits; Fatty acid glycerol esters; Goals; Health; 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; Research; Risk; Structure; Study Subject; Subgroup; Testing; Woman; Women' s Health; adverse outcome; base; cancer health disparity; cancer risk; cardiovascular risk factor; cohort; cytokine; diabetes risk; disadvantaged population; effective intervention; experience; glucose tolerance; high risk; improved; improved outcome; inflammatory marker; inhibitor/antagonist; innovation; malignant breast neoplasm; monocyte; mortality; neoplastic cell; novel; obesity risk; outcome forecast; population based; standard of care; study population; 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）：肥胖的免疫代谢并发症与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，这一群体受到的影响尤为严重。胰岛素抵抗性肥胖的特点是脂肪的慢性全身性和局部炎症，这与乳腺癌的结局有关。然而，并不是所有的肥胖都会带来同样的癌症风险。大约四分之一的肥胖非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。最近对弗雷明汉研究人群数据的分析表明，这些受试者患肥胖相关癌症（包括乳腺癌）的风险也有所降低。这些健康肥胖成年人的一个关键特征是炎症减少，无论是局部脂肪还是全身血液。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”的肥胖非裔美国妇女是否有较少的乳腺组织或全身炎症，也不知道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预防乳腺癌；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，并使用基础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肥胖女性癌症风险分层的关键免疫代谢机制，并在乳腺癌细胞培养模型中测试假设的关系。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；治疗胰岛素抵抗性肥胖的标准药物二甲双胍对非洲预防乳腺癌有价值