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.

肥胖承认增加了各种形式癌症的风险。乳腺癌，结肠和肝癌都是 肥胖人群的增加和肥胖的流行病学证据 - 乳腺癌的联系是 引人注目。八分之一的女性将在她的一生中被诊断出患有乳腺癌。乳腺癌是 与年龄相比，年龄与年龄相比，与年龄相比，年龄与年龄密切相关的年龄增加了10倍 S50。随着年龄的增长，风险增加似乎与肥胖后的绝经后激素水平有关 高胰岛素血症与不骑马的女性中的乳腺癌风险增加有关 替代疗法。代谢综合征与更高的侵略性三重阴性发生率有关 乳腺肿瘤（er-/pr-/her2-）可能会因更年期后的卵巢果子下降而加速，如 绝经后妇女更容易受到肥胖的有害代谢作用的影响 慢性炎症和胰岛素抵抗。啮齿动物研究已经证实了这种关系，表明 饮食引起的肥胖症和高脂肪饮食会导致各种乳房中肿瘤的发病率增加和生长 癌症模型。尽管有相关的证据，但肥胖引起的乳腺癌的机制 风险仍然很少理解。饮食成分是一个重要因素，因为饮食富含饱和和欧米茄6 （W6）脂肪酸（FAS）是促炎的，乳腺癌风险增加，但富含欧米茄3（W3）的饮食 FA是抗炎的，降低了癌症的风险。临床数据不太清楚，但是 多次人类乳腺癌风险研究表明，OO6与W3 FAS的比率是关键因素。 我们发现，有益的抗炎和胰岛素敏感性0）3 fas是 由G蛋白偶联受体GPR120介导。由于肥胖，胰岛素之间的潜在联系 绝经后妇女的抗药性和乳腺癌风险，我们假设GPR120是关键 W3 FAS在乳腺癌中受保护作用的介体。我们将以四个特定目标进行测试 结合1）使用原位肿瘤细胞移植和2）肥胖野生型的自发肿瘤的研究 （WT）和GPR120敲除（KO）小鼠，补充W3 FA，3）使用原位小鼠和 人类肿瘤细胞移植到RAG2 KO小鼠中，4）使用一般标记的转移研究 肥胖WT和GPR120 KO小鼠中的肿瘤细胞。我们假设u）3 FA会衰减肿瘤发生 通过抗炎/胰岛素敏化作用 该项目旨在为项目2和3的目标提供完整的机械深度。