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Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an “insulin sensitizer” because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment. (Cancer Res 2006; 66(21): 10269-73)

Supplementary Figure 1 from Metformin Is an AMP Kinase–Dependent Growth Inhibitor for Breast Cancer Cells

Breast cancer (BC) prognosis and outcome are adversely affected by increased body weight, obesity and the obesity-associated type 2 diabetes. Hyperinsulinemia, which is commonly seen as part of metabolic reprograming in the obese state, has been associated with higher risk of death and recurrence in BC. Up to 80% of breast cancers overexpress the insulin receptor (INSR) de novo, which correlates with worse prognosis. To directly probe the role of insulin signaling in mammary tumorigenesis in the mouse, we generated the MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC models, respectively, with coordinate mammary epithelium-restricted deletion of the INSR. In both models, deletion of either one or both copies of the INSR in the mammary gland led to a marked delay in tumor onset and burden, including in mice fed to mimic conditions of human obesity. Longitudinal monitoring of generated mouse models revealed that tumor initiation, rather than progression and metastasis, were impacted by INSR deletion. The similarity of phenotypes elicited by the deletion of one or both copies of INSR raises the possibility that there is a dose-dependent threshold for the contribution of INSR to mammary tumorigenesis.