Abstract BACKGROUND: Obesity and type II diabetes have been linked to a higher risk of breast cancer in post-menopausal women. Patients treated with the anti-diabetic drug metformin (1,1-dimethylbiguanide hydrochloride) for type II diabetes or metabolic syndrome have shown a reduced risk of breast cancer, a greater pathologic complete response for neoadjuvant therapy and an improved breast cancer survival. The purpose of this study was to examine the effects of metformin on tumor promotion in a rodent model of obesity and postmenopausal breast cancer. METHODS: Rats were injected with N-methylnitrosourea (MNU, 50 mg/kg) at 8 weeks of age to induce mammary tumors, and fed a high fat diet (from 5 weeks of age) to promote obesity. Obesity-resistant and obesity-prone rats were selected, based upon weight gain (between 10 and 14 weeks of age) and were matured under these conditions to produce adult, tumor-bearing lean and obese rats (24±1 vs 29±1 % body fat). Tumors were monitored by manual palpation at weekly intervals from the time of MNU administration. Obese animals were randomly assigned to either metformin treatment (2mg/mL in their drinking water, n=8) or control group (water only, n=6), after at least 1 tumor reached a volume >1cm3. Rats were maintained on their respective treatments for the duration of the study. One week following the initiation of treatment, animals were ovariectomized (OVX) to mimic the post-menopausal state, and tumor palpations were continued for an additional 9 weeks. RESULTS: Prior to OVX, control and metformin treated obese rats were similar in weight (413±21 vs 397±20 g) and tumor burden (3.3±1.2 vs 3.7±2.3 g). In response to OVX, tumor burden decreased in all animals, as predicted, based on the hormone responsiveness of MNU-induced tumors. Compared to untreated obese rats, the percent of pre-OVX tumor burden was lower in metformin-treated rats (weeks 1-3 post-OVX; 67±10 vs 26± 8%, p<0.05). A tendency for metformin to attenuate the subsequent rebound in tumor burden was observed at week 7 (126±67 vs 41±35%, p=0.06), week 8 (170±112 vs 35±29%, p=0.06), and week 9 (249±165 vs 41±30%, p=0.09). CONCLUSIONS: These preliminary observations indicate that metformin enhances OVX-induced tumor regression in obese rats and may reduce long term tumor growth and survival in these animals after the surgery. These findings suggest that metformin may have therapeutic benefits in obese, peri- or post-menopausal patients who are at risk for breast cancer. 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 72.