Abstract 1341: Insulin directly induces endometrial cell proliferation and carcinogenesis

Abstract Introduction: Diabetes and insulin resistance are strong risk factors for type 1 endometrial cancer. The mitogenic actions of insulin are well described, but less is known about the role insulin may play in carcinogenesis. It is unknown if insulin plays direct role in the carcinogensis of endometrial cells or if insulin promotes carcinogenesis through its overall physiological effects. Key pathways within the insulin signaling cascade, such as Ras-MAPK and PI3-K-mTOR, are also involved in the formation and progression of many cancers. The goal of this study was to determine if insulin exerted direct effects on normal endometrial cell proliferation and carcinogenesis. Methods: The effects of varying doses of insulin on endometrial cells collected from human menstrual blood from healthy volunteers were measured using a standard MTS cytotoxicity assay. These cells were also grown in 3-D organotypic culture for 2 weeks and exposed to a known carcinogen, 7, 12-dimethylbenz[α]anthracene (DMBA), insulin, and the combination of both agents. Effects of insulin were evaluated by histological evaluation and quantified with anchorage independent growth assays. Results: Insulin increased proliferation of endometrial cells in a dose dependent fashion. In the organotypic model, insulin caused the development of malignant features such as nuclear pleomorphism, hyperchromasia, and mitosis as a single agent and enhanced these malignant features in the DMBA treated cultures. Consistent with these findings, soft agar colony forming assays demonstrated significantly greater numbers of anchorage-independent colonies in cultures treated with insulin plus DMBA in comparison to cultures treated with DMBA alone. Conclusions: Insulin exerts direct effects on endometrial cells by increasing their proliferation and enhancing their susceptibility to carcinogenesis. Western immunoblotting is now being performed to characterize the effects of insulin on the AKT and MAPK signaling pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1341. doi:10.1158/1538-7445.AM2011-1341