Abstract B48: Lack of efficacy of the anti-diabetic drug metformin in the ER+ methylnitrosourea (MNU)-induced and the ER- MMTV-Neu/p53KO models of mammary cancer

Abstract

Abstract Metformin, an anti-diabetic drug, activates AMP-activated protein kinase (AMPK), and has generated a great deal of interest as a potential preventive agent for a variety of cancers, including breast. This interest is based both on epidemiologic studies showing that diabetics treated with metformin have a lower incidence of a variety of cancers, and on mechanistic considerations arguing that activation of AMPK is likely to be relevant to cancer treatment and prevention. We examined the preventive efficacy of metformin in ER+ and ER- rodent mammary cancer models. Treatment of Sprague-Dawley female rats at 50 days of age with a single dose of MNU (75 mg/kg BW) resulted in the development of multiple ER+ mammary cancers beginning approximately 7 weeks after MNU treatment. This model has been highly responsive to a wide variety of agents that affect ER+ tumors in humans (SERMs, aromatase inhibitors, pregnancy, ovariectomy). Metformin was administered by gavage (7x/week) at either 150 or 50 mg/kg BW/day beginning 7 days after MNU dosing, and continuing for the duration of the study. Metformin failed to decrease mammary tumor incidence and, in fact, increased tumor multiplicity in this model by approximately 35%. In addition, we are evaluating the ability of metformin to inhibit mammary cancer in MMTV-Neu/p53KO mice (which spontaneously develop ER- cancers). In this study, metformin was administered in the diet at a dose level of 1500 mg/kg diet. Initial supplementation of the diet with this agent began when the mice were 60 days of age, and will continue for 10 months. This study similarly has shown no preventive efficacy of metformin (av. tumors/mice: controls, 2.1; metformin, 2.5). Thus, these initial studies fail to observe any chemopreventive efficacy of metformin in two commonly employed models of ER+ and ER- mammary cancers in rodents. Supported by NCI contract number HHSN261200433001C. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B48.