Abstract 3609: Metformin treatment outcomes in relation to obesity and cation transporter expression in mouse models of endometrial cancer

Purpose: Obesity is associated with increased risk and worse outcomes for endometrial cancer (EC). Metformin, a frontline therapy for type 2 diabetes, is thought to have both indirect and direct anti-cancer effects via decreasing circulating insulin/glucose and activating AMPK/inhibiting mTOR signaling, respectively. Due to its positive charge (pKa 12.4) and hydrophilicity (logD -6.13 at pH 7.4), metformin requires cation transporters for cellular uptake where it can then activate AMPK; and thus, variation in transporter expression may be critical for response to metformin for cancer treatment. Thus, we explored the inter-relationship of obesity, cation transporter expression and the anti-tumorigenic efficacy of metformin in a genetically engineered endometrioid EC mouse model. Methods: LKB1fl/fl p53fl/fl mice were fed a low-fat diet (10% calories from fat) vs. a high-fat diet (60% calories from fat) to mimic diet-induced obesity, starting at 3 weeks of age (n=10 mice/group). AdCre was injected at 6 weeks of age to induce EC. Mice were treated for four weeks with placebo or metformin (200 mg/kg/day, oral gavage) following tumor onset. Cell proliferation/apoptotic markers and downstream targets of AMPK/mTOR signaling were evaluated in the ECs by immunohistochemistry. Cation transporter expression was assessed in the ECs by Western blotting and RNA sequencing. Results: Obesity led to a doubling of endometrial tumor size in obese vs. lean mice (1.469g vs. 0.75g). Metformin was more potent in inhibiting tumor growth in obese vs. lean mice (78% vs. 60%) compared to the respective controls (p