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

肥胖会增加患各种癌症的风险。乳腺癌结肠癌肝癌都是 肥胖人群增加，肥胖与乳腺癌联系的流行病学证据是 引人注目。八分之一的女性在一生中会被诊断出患有乳腺癌。乳腺癌是 与年龄密切相关，260岁女性的发病率是260岁女性的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，因为肥胖和 高胰岛素血症仅在未使用激素妇女中与乳腺癌风险增加相关 替代疗法代谢综合征与侵袭性三阴性的发生率较高相关 乳腺肿瘤（ER-/PR-/HER 2-），这可能是加速卵巢激素下降绝经后， 绝经后妇女更容易受到肥胖症的有害代谢影响， 慢性炎症和胰岛素抵抗。啮齿动物研究证实了这种关系，表明， 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， 癌症模型。尽管有这些相关的证据，肥胖诱发乳腺癌的机制 风险仍然知之甚少。饮食组成是一个重要因素，因为饮食中富含饱和脂肪酸和欧米伽6 (w6)脂肪酸（FAs）是促炎性的，会增加乳腺癌的风险，但富含欧米伽3（w3）的饮食 脂肪酸是抗炎和降低癌症风险。临床数据不太清楚，但荟萃分析显示， 多项人类乳腺癌风险研究表明oo 6与w3脂肪酸的比例是一个关键因素。 我们已经发现，0.3脂肪酸的抗炎和胰岛素增敏作用是有益的， 由G蛋白偶联受体GPR 120介导。由于肥胖和胰岛素之间的潜在联系 在绝经后妇女中，GPR 120与乳腺癌的发病风险有关，我们假设GPR 120是决定乳腺癌发病风险的关键因素。 W3 FAs在乳腺癌中保护作用的介导者。我们将在四个具体目标中对此进行测试， 联合收割机1）使用原位肿瘤细胞移植的研究和2）肥胖野生型中的自发性肿瘤 (WT)和GPR 120敲除（KO）小鼠，3）使用原位小鼠和 人肿瘤细胞移植到RAG 2 KO小鼠中，和4）使用遗传标记的转移研究 肥胖WT和GPR 120 KO小鼠中的肿瘤细胞。我们假设，α 3脂肪酸将减弱肿瘤发生， 通过其抗炎/胰岛素增敏作用在WT而非GPR 120 KO小鼠中的转移 这个项目旨在提供机械的深度，是补充项目2和3的目标。

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.