Role of Inflammation and Insulin Resistance in Mouse Models of Breast Cancer

炎症和胰岛素抵抗在小鼠乳腺癌模型中的作用

• 批准号: 8072501
• 负责人: jerrold Michael OLEFSKY
• 金额: $ 25.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-07 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072501
• 关键词: Adverse effects; Age; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Attenuated; Back; Basement membrane; Blood Circulation; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Risk Factor; Calories; Carcinoma; Cell Surface Receptors; Cell Transplants; Cells; Chronic; Clinical Data; Colon Carcinoma; Data; Diagnosis; Diet; ERBB2 gene; Energy Intake; Epidemiology; Epithelial Cells; Fatty Acids; Fatty acid glycerol esters; Female; Fish Oils; G-Protein-Coupled Receptors; Growth; Hormone replacement therapy; Hormones; Human; Hyperinsulinism; Hyperplasia; Immune system; Incidence; Inflammation; Inflammatory; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Lead; Link; Malignant Neoplasms; Malignant neoplasm of liver; Mammary Neoplasms; Mammary gland; Measures; Mediating; Mediator of activation protein; Menopause; Meta-Analysis; Metabolic; Metabolic syndrome; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Obese Mice; Obesity; Omega-3 Fatty Acids; Ovarian hormone; Phenotype; Polyomavirus; Postmenopause; Premenopause; Primary Neoplasm; Risk; Rodent; Role; Simulate; Staging; Supplementation; T-Lymphocyte; Tail; Testing; Time; Tissues; Transplantation; Tumor Tissue; Woman; adenoma; base; cancer risk; cytokine; feeding; insulin sensitivity; male; malignant breast neoplasm; metabolic abnormality assessment; mouse model; neoplastic cell; novel; protective effect; receptor; tumor; tumor growth; tumor initiation; tumorigenesis

Obesity confers increased risk for various forms of cancer. Breast, colon, and liver cancer are all increased in obese populations and the epidemiologic evidence for the obesity - breast cancer connection is compelling. One in eight women will be diagnosed with breast cancer during her lifetime. Breast cancer is strongly associated with age as incidence increases 10-fold for women age 260 compared to women age S50. Increased risk with age seems related to post-menopausal hormone levels as both obesity and hyperinsulinemia are associated with increased breast cancer risk only in women not on hormone replacement therapy. Metabolic Syndrome is associated with a higher incidence of aggressive triple negative breast tumors (ER-/PR-/HER2-) which is likely accelerated by ovarian hormone decline after menopause, as post-menopausal women are more susceptible to the deleterious metabolic effects of obesity including chronic inflammation and insulin resistance. Rodent studies have confirmed this relationship, showing that diet-induced obesity and high fat diets lead to increased incidence and growth of tumors in various breast cancer models. Despite this body of correlative evidence, the mechanisms of obesity-induced breast cancer risk remain poorly understood. Diet composition is an important factor as diets rich in saturated and omega 6 (w6) fatty acids (FAs) are pro-inflammatory and increase breast cancer risk, but diets rich in omega 3 (w3) FAs are anti-inflammatory and decrease cancer risk. The clinical data is less clear but meta-analyses of multiple human breast cancer risk studies suggest that the ratio of oo6 to w3 FAs is a critical factor. We have found that the beneficial anti-inflammatory and insulin-sensitizing effects of 0)3 FAs are mediated by the G-protein coupled receptor GPR120. Due to the potential link between obesity, insulin resistance and breast cancer risk in post-menopausal women, we hypothesize that GPR120 is the critical mediator of the protective effects of w3 FAs in breast cancer. We will test this in four specific aims that combine 1) studies using orthotopic tumor cell transplants and 2) spontaneous tumors in obese wild type (WT) and GPR120 knockout (KO) mice, ¿ w3 FA supplementation, 3) studies using orthotopic mouse and human tumor cell transplants into RAG2 KO mice, and 4) studies of metastasis using genetically marked tumor cells in obese WT and GPR120 KO mice. We hypothesize that u)3 FAs will attenuate tumorigenesis and metastasis in WT but not GPR120 KO mice through their anti-inflammatory/insulin-sensitizing actions This project aims to provide mechanistic depth that is complementary to aims of Projects 2 & 3.

肥胖会增加患各种癌症的风险。 肥胖人群的增加以及肥胖与乳腺癌之间关系的流行病学证据是 八分之一的女性在其一生中会被诊断出患有乳腺癌。 与年龄密切相关，260 岁女性的发病率是同龄女性的 10 倍 S50. 随着年龄的增长，风险增加似乎与绝经后激素水平有关，如肥胖和绝经后激素水平。 高胰岛素血症仅在未服用激素的女性中与乳腺癌风险增加相关 替代疗法与侵袭性三阴性的较高发生率相关。 乳腺肿瘤（ER-/PR-/HER2-）可能会因绝经后卵巢激素下降而加速，如 绝经后妇女更容易受到肥胖的有害代谢影响，包括 慢性炎症和胰岛素抵抗的研究证实了这种关系。 饮食引起的肥胖和高脂肪饮食导致各种乳腺肿瘤的发病率和生长增加 尽管有大量相关证据，肥胖诱发乳腺癌的机制仍然存在。 饮食成分是一个重要因素，因为饮食中富含饱和脂肪酸和欧米伽 6，但人们对这一风险仍知之甚少。 (w6) 脂肪酸 (FA) 具有促炎作用，会增加患乳腺癌的风险，但富含 omega 3 的饮食 (w3) FA 具有抗炎作用并降低癌症风险，但临床数据尚不明确，但荟萃分析表明。 多项人类乳腺癌风险研究表明，oo6 与 w3 FA 的比例是一个关键因素。 我们发现 0)3 FA 的有益抗炎和胰岛素增敏作用是 由 G 蛋白偶联受体 GPR120 介导，由于肥胖与胰岛素之间存在潜在联系。 绝经后女性的耐药性和乳腺癌风险，我们认为 GPR120 是关键 我们将在四个具体目标中测试这一点。 结合 1) 使用原位肿瘤细胞移植的研究和 2) 肥胖野生型的自发肿瘤 (WT) 和 GPR120 敲除 (KO) 小鼠，¿ w3 FA 补充，3) 使用原位小鼠进行研究 将人类肿瘤细胞移植到 RAG2 KO 小鼠中，以及 4) 使用基因标记进行转移研究 肥胖 WT 和 GPR120 KO 小鼠中的肿瘤细胞我们发现 u)3 FA 会减弱肿瘤发生。 通过其抗炎/胰岛素增敏作用，在 WT 小鼠中发生转移，但在 GPR120 KO 小鼠中则不然 该项目旨在提供与项目 2 和 3 的目标相补充的机制深度。