Abstract
BackgroundObesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Patients treated with the antidiabetic drug metformin for diabetes or metabolic syndrome have reduced breast cancer risk, a greater pathologic complete response to neoadjuvant therapy, and improved breast cancer survival. We hypothesized that metformin may be especially effective when targeted to the menopausal transition, as this is a lifecycle window when weight gain and metabolic syndrome increase, and is also when the risk for obesity-related breast cancer increases.MethodsHere, we used an 1-methyl-1-nitrosourea (MNU)-induced mammary tumor rat model of estrogen receptor (ER)-positive postmenopausal breast cancer to evaluate the long-term effects of metformin administration on metabolic and tumor endpoints. In this model, ovariectomy (OVX) induces rapid weight gain, and an impaired whole-body response to excess calories contributes to increased tumor glucose uptake and increased tumor proliferation. Metformin treatment was initiated in tumor-bearing animals immediately prior to OVX and maintained for the duration of the study.ResultsMetformin decreased the size of existing mammary tumors and inhibited new tumor formation without changing body weight or adiposity. Decreased lipid accumulation in the livers of metformin-treated animals supports the ability of metformin to improve overall metabolic health. We also found a decrease in the number of aromatase-positive, CD68-positive macrophages within the tumor microenvironment, suggesting that metformin targets the immune microenvironment in addition to improving whole-body metabolism.ConclusionsThese findings suggest that peri-menopause/menopause represents a unique window of time during which metformin may be highly effective in women with established, or at high risk for developing, breast cancer.
Highlights
Obesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women
In a rodent model of estrogen receptor (ER)+ postmenopausal breast cancer we have shown that, during ovariectomy (OVX)-induced weight gain, an impaired ability to clear excess nutrients from the circulation and store them in mammary adipose tissue correlated with tumor glucose uptake, markers of proliferation, and tumor progression [23]
Metformin did not significantly affect food intake during either the early or late post-OVX period (Fig. 1d); it was not surprising that we found no differences in weight gain between the metformin-treated and control groups (Fig. 1c)
Summary
Obesity and type II diabetes are linked to increased breast cancer risk in postmenopausal women. Over the past several years, many studies have reported decreased breast cancer incidence and/or mortality in diabetics receiving the widely prescribed antidiabetic drug metformin relative to those receiving other diabetic drugs [1,2,3]. These studies have found a dose-response relationship whereby women receiving the highest metformin dose for the longest duration show the most benefit [4, 5]. There is ongoing interest in identifying patient populations who may benefit from metformin treatment, and the mechanisms by which metformin decreases cancer risk and/or improves tumor outcomes
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