Journal Article

Metformin inhibits stromal aromatase expression and tumor progression in a rodent model of postmenopausal breast cancer

Wellberg, Elizabeth A., Edwards, Dean P., Jindal, Sonali, MacLean, Paul S., Anderson, Steven M., Schedin, Pepper, Schedin, Troy, Giles, Erin D., Thor, Ann D.

2018

Overview

Background Obesity 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. Methods Here, 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. Results Metformin 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. Conclusions These 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adipose / Adipose tissue / Adjuvant chemotherapy / Analysis / Antidiabetics / Aromatase / Biomedical and Life Sciences / Biomedicine / Body weight / Body weight gain / Breast cancer / Calories / Cancer Research / Care and treatment / Development and progression / Diabetes mellitus / Dosage and administration / Estrogen receptors / Health aspects / Health risk assessment / Liver / Long-term effects / Macrophage / Macrophages / Mammary gland / Menopause / Metabolic syndrome / Metabolism / Metformin / Obesity / Oncology / Ovariectomy / Post-menopause / Postmenopausal women / Research Article / Risk factors / Rodents / Surgical Oncology / Tumor microenvironment / Tumors / Women's health / Womens health