MTOR Inhibition and Diet Induced Obesity in a Mouse Model of Postmenopausal Breast Cancer.

Abstract

Abstract Background:Breast cancer is the most common type of noncutaneous cancer among white women. It is more frequently diagnosed after menopause, and the majority of cases are estrogen receptor positive (ER+). Obesity is associated with poor prognosis, increasing risk by 50% in post-menopausal women, and correlates with shorter disease-free and overall survival. Unfortunately, the mechanism underlying the poorer outcomes in obese breast cancer patients is not known. The majority of ER+ tumors present with genomic ER activity; however, nongenomic ER activity can also occur, resulting in interaction with growth factor (GF) receptors.In the obese state nongenomic activity may be especially enhanced, promoting ER and GF signaling crosstalk, breast tumor cell growth and survival. Since Akt/mTOR signaling has been implicated in breast cancer, and obesity (through activation of GF signaling pathways) can activate this pathway, we hypothesized that the enhancement of tumor growth in response to obesity can be offset by mTOR inhibition. To test this we used a mouse model of postmenopausal breast cancer and investigated the effects of obesity (relative to lean and overweight phenotypes) with and without pharmacologic mTOR inhibition by RAD001.Methods:Ovariectomized C57BL/6 mice were randomized to diet regimens that induce either a lean, control (overweight), or a diet-induced obesity (DIO) phenotype. After 17 weeks on the diets, DIO mice were switched to the control diet and acclimated for 3 weeks. To determine diet-induced changes in adiposity, quantitative magnetic resonance (qMR) was performed at wk 18. At wk 21 mice were injected with syngeneic MMTV-Wnt-1 mammary tumor cells in the 4th mammary fat pad. Two weeks after tumor injection, the mice received RAD001 (10 mg/kg) or vehicle by oral gavage twice a week for 6 weeks.Tumor growth was measured weekly.Results:At week 17, mice in the DIO group were significantly heavier (42.8 g) than control (34.5 g) and lean mice (24.6 g) (p <0.001) and % fat was also higher (p<0.001) in DIO (54.5%) when compared to the control (42.2%) and lean (30.7%) groups.Tumor growth was different between the three diet regimens, confirming that dietary modulation directly influences MMTV-Wnt-1 tumor growth in a postmenopausal mouse model of breast cancer. DIO mice displayed significantly enhanced tumor growth (p<0.05) when compared to the control and lean mice. Overall, RAD001 was effective at decreasing tumor growth in all diet groups (p<0.01). However, the relative effect of RAD001 versus placebo was diminished in DIO mice compared to control and lean mice, suggesting obese mice may be partially resistant to RAD001. This resistance was overcome in the DIO mice by increasing the RAD001 dose to 15 mg/kg.Conclusion:Our results confirm that DIO increases tumor growth in the context of postmenopausal breast cancer. In addition, treatment with the mTOR inhibitor RAD001 reversed the mammary tumor enhancing effects of obesity (particularly at the higher dose of RAD001), further supporting mTOR as an important molecular target for breaking the obesity-breast cancer link. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5077.