Targeting the menopause transition with metformin improves breast cancer outcomes, but discontinuation has deleterious effects on metabolic health: Findings from a preclinical model of postmenopausal breast cancer
Abstract
BACKGROUND: Women with obesity and/or type-II-diabetes have an increased breast cancer risk, increased metastasis, and poorer prognosis, especially after menopause. In a rat model of high-fat-diet and menopause-induced weight gain, we previously reported that treatment with the anti-diabetic drug metformin for 8-weeks after ovariectomy (OVX; modeling menopause) reduced growth of existing mammary tumors and inhibited new tumor formation. This identified the menopause transition as a potential window-of-opportunity for interventions to decrease obesity-associated breast cancer incidence and disease progression. Here, we extend these findings to determine if limiting metformin to the peak window of OVX-induced weight gain would have similar anti-cancer effects.
FINDINGS: Metformin during the first four weeks following OVX is critical to reducing tumor burden, as rats treated with metformin early (weeks0-4-postOVX) had reduced tumor burden. Conversely, initiating metformin later in the postOVX period (weeks 4-8postOVX) did not reduce cancer burden. Despite improved tumor outcomes, metformin withdrawal after the early postOVX time had detrimental metabolic effects, including weight gain and increased adiposity, insulin, IGF1, and HOMA-IR, which correlate with increased cancer risk.
CONCLUSIONS: These data reveal early-postmenopause as a critical window when metformin decreases progression of existing disease and highlights the importance of maintaining treatment to prevent…
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