There has been increasing interest in metformin as an anticancer agent particularly for breast cancer prevention. Support for metformin in this capacity includes that this compound is considered to be a calorie restriction mimetic. Calorie restriction is well known to prevent the development of spontaneous, carcinogen-induced and transgenic mammary tumor development in rodent models of breast cancer. However, few studies have addressed how calorie restriction impacts the development of mammary tumors in obese animals despite the fact that initial application of this intervention in humans would likely be in overweight and obese women whose postmenopausal breast cancer risk is elevated by their body weight status. Further, direct comparisons of metformin to calorie restriction have rarely been reported. The goal of the present investigation is to compare the effect of metformin treatment and moderate calorie restriction on mammary tumor development in an obese mouse model of breast cancer. MMTV-TGF-α/C57BL6 female mice which develop mammary tumors in the second year of life will be used. Previous studies have shown that calorie restriction delays mammary tumor detection and reduces incidence (CEBP 11:836,2002; Exp.Biol.Med.232:70,2007) while obesity shortens latency and results in detection of high grade adenocarcinomas (Int.J.Obesity 28:956,2004; Breast Cancer Res. 9:R21,2007) in MMTV-TGF-α mice. At 10 weeks of age 3/4 of the experimental mice are fed a moderately high fat diet (33% by calories) and the other 1/4 maintained on AIN-93M diet until 30 weeks of age. Then high fat diet mice are divided into Obesity-Prone, Overweight and Obesity-Resistant groups based on weight gain. Within each weight group mice are further divided into ad libitum-fed, ad libitum-fed+metformin (250 mg/kg bw/day in the diet) or calorie restricted by 25%. These same interventions are applied to the Control AIN-93M mice. Final group sizes are ∼32 mice. Daily food intakes are measured and mice monitored weekly for mammary tumor status and to obtain body weights. Blood samples will be obtained at specified time points until 90 weeks of age. Two weeks prior to euthanasia mice will be given a bolus of deuterated water followed by inclusion of deuterated water in their drinking water until death. This will allow determination of in vivo cell proliferation in mammary tissues and tumors. Serum will be analyzed for insulin, IGF-I and glucose responses to these interventions. Also liver and mammary tissues will be obtained to compare the effects of metformin and calorie restriction on putative mechanistic pathways related to AMPK. Results of this study will clarify aspects of both metformin's and calorie restriction's effects on mammary tumor prevention with respect to body weight status.

Supported by NIH-NCICA157012 and The Hormel Foundation.

Citation Format: Michael E. Grossmann, Nancy K. Mizuno, Margot P. Cleary. A comparison of metformin treatment and moderate calorie restriction on mammary tumor development in obese mice. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B102.