The novel findings presented here are 1) that metformin inhibits the proliferation of most cultured breast cancer cell lines and that this does not correlate with the status of ER, Her-2, or p53 expression; 2) cyclin D1 levels are sharply downregulated in response to metformin but this alone is not sufficient to cause cell cycle arrest; and 3) cell cycle arrest also requires sufficient levels of CDK inhibitors (i.e. p27Kip1 or p21Cip1) to bind and inhibit CDK2. This evidence concerns the gene ESR1 and breast carcinoma.