Abstract 1847: Effect of rapamycin and metformin on skin tumor promotion in mice overweight and obese

Abstract

Abstract The prevalence of obesity in the US has risen drastically over the past few decades and is an established risk factor for several human cancers. Insights into the mechanisms underlying this link are urgently needed to develop strategies for treatment and prevention. Various studies have shown that calorie restriction (CR) during tumor promotion in the two-stage model of skin carcinogenesis causes a significant reduction in tumorigenesis. In addition, diet induced obesity (DIO) leads to insulin resistance, increased circulating levels of IGF-1 and increased susceptibility to tumor development. Current data indicate that signaling through the IGF-1R and EGFR as well as several downstream signaling pathways plays an important role in dietary energy balance effects on tumor promotion during epithelial carcinogenesis. The current study was designed to evaluate the ability of rapamycin (an established mTORC1 inhibitor) to inhibit or reverse the effects of overweight/obesity on skin tumor promotion in mice. In initial experiments using female FVB mice on an AIN76A diet, rapamycin (5-1000 nmol per mouse) was found to be a potent inhibitor of skin tumor promotion by TPA. In this regard, rapamycin reduced both tumor multiplicity and incidence in a dose dependent manner. A dose of 5 nmol rapamycin given 30 min before each TPA treatment reduced the number of papillomas per mouse by approximately 50%. Rapamycin treatment inhibited TPA-induced mTORC1 activation as well as downstream signaling proteins p70S6KT389, prS6S240/244 and p4EBP1T37/46. Multiple treatment experiments were performed to evaluate the effects of rapamycin (5-200 nmol per mouse) on TPA-induced epidermal hyperproliferation (as assessed by epidermal hyperplasia and epidermal labeling index). Rapamycin significantly inhibited TPA-induced epidermal hyperproliferation in a dose dependent manner. In addition, immunohistochemical analyses of the skin from mice in this multiple treatment experiment revealed that rapamycin significantly decreased the number of infiltrating macrophages, T-cells, neutrophils, and mast cells seen in the dermis following TPA treatment. Moreover, topical application of rapamycin to existing papillomas induced regression and/or inhibited their growth. Two-stage skin carcinogenesis studies are currently underway to further evaluate the impact of rapamycin treatment on mice made overweight (AIN76A) or obese (DIO diet; 60 Kcal % fat) via dietary energy balance manipulation. In addition, groups of mice are also being treated with metformin. These ongoing studies will clarify whether suppression of the mTORC1 signaling pathway is a viable strategy for reversing the effects of obesity on tumor development in this well established model of epithelial carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1847. doi:10.1158/1538-7445.AM2011-1847