Abstract 621: Effect of diet-induced obesity on MCF-7Ca xenografts grown in ovariectomized athymic nude mice

Abstract

Abstract Obesity has been identified as one of the risk factor for breast cancer progression. However the mechanisms underlying this link are not completely understood. Specifically, breast cancer patients who are overweight, obese or have excess abdominal fat have increased risk of local or distant (metastasis) recurrence and cancer related death. Furthermore, breast cancer patients gain weight during treatment, especially those who receive hormone depletion therapies, are at increased risk of developing obesity and metabolic syndrome in surviving patients. Importantly, the presence of obesity may influence the resistance of breast cancer to existing treatments, such as aromatase inhibitors (AIs). In an effort to understand the effect of obesity on the growth of hormone dependent breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat (45% of the total calories coming from the fat in the diet) and low fat (10% kcal fat) diet. We saw that mice fed with 45%kcal fat diet had a higher rate of tumor growth (p=0.04) compared to mice that were fed with 10% kcal fat containing diet. In addition, the mice fed with 45% kcal fat had higher body weight and also higher level of insulin, as measured by C-peptide ELISA. Next, we examined the effect of insulin on the growth of MCF-7Ca cells in response to E2 or letrozole. When co-treated with 2μM of exogenous insulin (in otherwise serum starved condition), the growth of MCF-7Ca cells was not stimulated by E2 at 1nM. However, at lower does, the combination of insulin with E2 stimulated cell growth more than E2 alone. This suggests that insulin makes MCF-7Ca breast cancer cells hypersensitive to mitogenic effects of E2. Hypersensitivity to E2 is one of the suggested mechanisms of resistance to endocrine therapy. Furthermore, response to anti-proliferative effects of letrozole was also abrogated in presence of insulin (2μM). This was more pronounced at lower dose of letrozole. These results suggest that the presence of insulin makes MCF-7Ca cells less responsive to E2 and letrozole. Furthermore, tumors of mice fed with high-fat diet also had higher activation of MAPK and Akt, suggesting induction of growth factor receptor pathways. Exogenous insulin treatment of MCF-7Ca cells also resulted in reduction of ERα protein levels and increase in p-MAPK and p-AKt. These results suggest that diet-induced obesity may result in acquisition of resistance to letrozole due to development of hyperinsulinemia. We hypothesized that the presence of obesity can augment adaptation of cancer cells and impact the mechanism. This may be the result of a dramatically different hormonal milieu upon development of obesity. Citation Format: Gauri J. Sabnis, Olga Goloubeva, Preeti Shah, Saranya Chumsri, Angela Brodie. Effect of diet-induced obesity on MCF-7Ca xenografts grown in ovariectomized athymic nude mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 621. doi:10.1158/1538-7445.AM2014-621