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

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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.