Abstract 1010: Effect of dietary energy balance modulation on the ability of metformin to inhibit skin tumor promotion

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The prevalence of obesity has drastically increased over the last decade and is associated with increased risk for several cancers. In contrast, calorie restriction (CR) universally inhibits cancer. Plausible mechanisms for the energy balance-cancer link include differential signaling through Akt/mTOR via the IGF-1R as well as other growth factor receptors. Previous data from our lab, using topical administration of rapamycin, support the hypothesis that pharmacological disruption of mTORC1 signaling mimics some of the effects of CR on skin tumor promotion. To further explore the role of mTORC1 signaling in tumor promotion we have conducted studies using metformin. In the present study, metformin was administered in the drinking water at doses of 250 mg/kg and 50 mg/kg body weight per day to female FVB/N mice, to assess its ability to reverse the effects of overweight/obesity on skin tumor promotion during two-stage skin carcinogenesis. Metformin treatment during skin tumor promotion significantly inhibited tumor multiplicity in a dose dependent manner in mice on an overweight control diet (AIN76A). There was a 70% reduction in papillomas per mouse at the 250 mg/kg dose and a 35% reduction at the 50 mg/kg dose. Short term mechanistic experiments with these same doses revealed significant decreases in TPA-induced epidermal hyperproliferation (as measured by epidermal hyperplasia and labeling index) after oral administration of metformin. Metformin also activated AMP Kinase in the epidermis as measured by pAMPKαT172 at both doses used as well as attenuated signaling through mTORC1 at the highest dose as measured by downstream signaling proteins p70S6KT389 and prS6S235/236. Treatment with the higher dose of metformin also prevented TPA-induced mTORC1 mediated degradation of translational repressor PDCD4. Current experiments are assessing the ability of metformin to suppress skin tumor promotion in mice maintained on an obesity inducing diet (60kcal% fat) and these studies will also be presented. Overall, the current data support the hypothesis that selectively targeting mTORC1, either directly (rapamycin) or indirectly via AMPK activation, may be an effective strategy for reversing the effects of overweight and obesity on tumor development during epithelial carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1010. doi:1538-7445.AM2012-1010