Type 2 diabetes and obesity metabolic interactions: common factors for breast cancer risk and novel approaches to prevention and therapy.

The objective was to review type 2 diabetes as a risk factor for breast cancer, its influence on tumor aggressiveness and prognosis, and the interactions with obesity. Consideration was given to the responsible biological mechanisms and how these relate to the potential of hypoglycemic agents, notably metformin, as breast cancer chemotherapeutic agents. Most epidemiological studies indicate that type 2 diabetes is a modest positive risk factor for postmenopausal, but not premenopausal, breast cancer; indeed before the menopause it may be associated with a reduced risk. This pattern of differing effects on risk according to menopausal status is well established in obesity; however, although most type 2 diabetics are obese, the relationship with postmenopausal breast cancer does not appear to be a function of the body mass index. We suggest that before menopause the protective effect of obesity may modify any adverse effects of the metabolic changes related to type 2 diabetes. Regardless of menopausal status, obesity is associated with breast cancers that exhibit aggressive biological characteristics at the time of diagnosis and have a poor prognosis; a similar relationship is emerging for type 2 diabetes. The two metabolic disorders share biological mechanisms for their associations with breast cancer, including a direct effect of insulin on breast cancer cell proliferation, increased extraglandular estrogen production and bioavailability, changes in the adipokines, notably adiponectin, and activation of the AMP-activated protein kinase pathway. These mechanistic considerations are consistent with metformin having high potential as a breast cancer chemopreventive and therapeutic agent.