Abstract 5085: Formerly obese mice display increased mmtv-wnt-1 tumor growth despite normalization of body weight: The role of mTOR

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Obesity, an established breast cancer risk factor in postmenopausal women, is also associated with poor prognosis and shorter disease-free and overall survival in pre-and postmenopausal breast cancer patients. It is not known if restoration of normal weight in obese individuals reverses the negative effects of obesity on mammary tumor progression. Since increased signaling through the mammalian target of rapamycin (mTOR) pathway has been implicated in breast cancer, and obesity can activate this pathway, we hypothesized that mTOR signaling remains activated and tumor growth high following weight loss in diet-induced obesity (DIO) mice, and that mTOR inhibition would offset this effect. Ovariectomized (OVX) C57BL/6 mice were randomized to diet regimens that induce a lean (calorie restricted; n=20), overweight (control; n=20), or DIO (n=30) phenotype. Following 17 weeks of diet treatment, quantitative magnetic resonance was performed on all mice, and the DIO mice were switched to the control diet. At week 20, all mice were injected with 5×104 syngeneic MMTV-Wnt-1 mammary tumor cells in the 4th mammary fat pad. Two weeks after tumor injection, 10 mice/diet group received RAD001 (10 mg/kg/body weight) and 10/group received placebo by oral gavage 2x/week for 6 weeks. The remaining 10 DIO mice received a higher dose of RAD001 (15 mg/kg/body weight). Tumor growth was measured 2x/week and serum levels of IGF-1 were measured at study endpoint. DIO mice were significantly heavier (47.4 ± 1.1) at week 17 than control (33.7 ± 0.6) and lean mice (25.3 ± 0.4); % body fat was also higher (p<0.001) in DIO (54.4%) compared to the control (41.7%) and lean (32.7%) mice. However, DIO mice lost weight after they were switched to the control diet, and their body weights matched the controls at the time of tumor cell injection. Tumor growth in formerly DIO mice was enhanced (p<0.05) compared to the control and lean mice. RAD001 was effective at decreasing tumor growth in all diet groups (p<0.01). The effect of RAD001 was diminished in the formerly DIO mice compared to control and lean mice, but this partial resistance was overcome with the higher RAD001 dose. RAD001 significantly increased serum IGF-1 levels in all groups. Gene expression microarray, Western blot, and immunohistochemical analyses of mTOR and other key growth and survival pathways are ongoing to identify pathways underlying the enhanced tumor growth in formerly obese mice. In conclusion, our results suggest that the growth-enhancing effects of obesity on mammary cancer may persist even after weight loss, due at least in part to activation of mTOR signaling that can be offset by RAD001 treatment. These findings suggest that a combination of dietary and pharmacologic interventions, such as mTOR inhibitors, may be required to break the obesity-cancer link. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5085.