Obesity, inactivity and type II diabetes have been associated with an increased risk of breast cancer. It is unclear whether lack of glucose control/abnormal gluconeogenesis is itself a risk factor, or whether the relationship is multifactorial. Recent evidence suggests that metformin, an FDA approved drug for type II diabetes, reduces the incidence and may improve the prognosis of several cancer types. It is increasingly prescribed to pre-diabetic patients as well. Metformin is a known AMP kinase-dependent growth inhibitor of breast cancer cells.

We studied the in vitro effects of metformin on several breast cancer cell lines including: MCF-7 (ER+, low erbB2), erbB2-transfected MCF-7, named MCF-7/713 (ER+, high erbB2), BT-474 (ERα+, high erbB2) and SKBR-3 (ER-, high erbB2). Metformin showed dose dependent, anti-proliferative and anti-colonogenic activity in all cell lines tested. Flow cytometric analyses revealed that metformin induced cell cycle arrest at the G1 checkpoint, with a reduction in cell entry into the S phase. Mechanistically, metformin treatment was associated with a decreased expression of Cyclin D1 and E2F-1. It had no significant effect on the expression of p21waf-1 or p27kip1. Phosphorylation of mitogen-activated protein kinase (MAPK) and Akt were also reduced by metformin treatment, suggesting inhibition of receptor tyrosine kinase signaling. At low doses, metformin inhibited erbB2 tyrosine kinase which was quantitated by an erbB2 autophosphorylation assay. Higher concentrations of metformin reduced erbB2 protein expression in addition to autophosphorylation. In summary, metformin can inhibit both ER + and ER - breast cancer cell growth through cell cycle arrest at the G1 checkpoint. In cells with erbB-2/HER2 abnormalities, metformin may reduce the pro-carcinogenic effects of the oncogene through a reduction in erbB2/HER2 expression and receptor autophosphorylation. The interruption of cell cycle progression and erbB-2/HER2 signaling activity induced by metformin may be of clinical use to treat or prevent breast cancer.

Research Supported by the Avon Foundation-AACR International Scholar Award in Breast Cancer Research. Grant # PN 2006 02-25.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA