TRANSPORTERS IN METFORMIN TREATMENT OF ENDOMETRIAL HYPERPLASIA

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DESCRIPTION (provided by applicant): Obesity and diabetes are strong risk factors for endometrial cancer and its precursor lesion, endometrial hyperplasia. Metformin, a generic oral anti-hyperglycemic, has been widely used to treat diabetes and gynecologic problems including anovulatory-related infertility and polycystic ovarian syndrome. Mounting epidemiological evidence suggests that metformin reduces cancer risk and cancer deaths among diabetic patients. Based on preclinical in vitro and in vivo studies, metformin demonstrates anti-proliferative effects for both endometrial hyperplasia and cancer through AMP-activated protein kinase (AMPK) activation and inhibition of the mTOR pathway. The only available treatment options for endometrial hyperplasia are progestin therapy or hysterectomy. However, side effects of progestins include increased appetite and weight gain which are particularly detrimental in a population prone to obesity and the metabolic syndrome. We hypothesize that metformin may offer an alternative treatment for endometrial hyperplasia and possibly confer secondary benefits including improvements in insulin resistance, weight loss, and normalization of menstrual cycles. Thus, we have an ongoing pilot clinical trial to assess the efficacy of metformin in the treatment of endometrial hyperplasia without atypia. Due to its physicochemical properties, metformin requires cation-selective transport proteins to traverse cell membranes. Studies show that very low levels of metformin transporter expression in some breast cancer cell lines significantly reduces cellular uptake of metformin. Since AMPK, the target of metformin that mediates its anti-proliferative effects is intracellular, it is expected that in the absence o metformin transporters or significantly low levels of metformin transporter expression, metformin would be ineffective as a treatment for endometrial hyperplasia/cancer. Thus, the aim of this study is (1) to determine metformin transporter expression in endometrial cancer/hyperplasia cell lines and tissue, and (2) to correlate metformin transporter expression with response to metformin treatment in an ongoing clinical trial of this agent for the treatment of endometrial hyperplasia. Other potential biomarkers of treatment response will also be explored and correlated with metformin transporter expression, including markers of metabolic syndrome and molecular markers of downstream targets of the metformin/mTOR signaling pathway. We hypothesize that expression of the metformin transporters will predict which women with endometrial hyperplasia will derive the greatest benefit from metformin treatment, and thus, be a critical component of future clinical trials of metformin for both endometrial hyperplasia and cancer.