Abstract 2197: Epithelial Mig-6 is critical for a tumor suppressor function in endometrial cancer

Abstract

Abstract Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) action. A bias toward E2 action and away from P4 action underlies the tumorigenesis of endometrial adenocarcinoma which is the fourth most common cancer in women. In previous studies, we have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of PR (progesterone receptor) action in the uterus. Mig-6 is expressed in both the epithelium and stroma of the uterus. Conditional ablation of Mig-6 in all compartments of the uterus (PRcre/+ Mig-6f/f) results in infertility and leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. Our central hypothesis is that Mig-6 is a critical mediator of stromal-epithelial communication in pregnancy, steroid hormone regulation and tumor suppressor function. In order to understand the role of epithelial Mig-6 in the uterus, we generated a mouse model in which we specifically ablate epithelial endometrial Mig-6 using Wnt7a-cre mice (Wnt7acre+ Mig-6f/f). Wnt7acre+ Mig-6f/f mice are subfertile due to embryo abortion and display normal P4 attenuation of E2-mediated uterine hypertrophy. However, Wnt7acre+ Mig-6f/f mice develop endometrial hyperplasia at 5 months of age as well as estrogen-induced endometrial cancer. The expression of PR is reduced in Wnt7acre+ Mig-6f/f mice compared to control Mig-6f/f mice. Interestingly, the hyperplasia exhibited by the Wnt7acre+ Mig-6f/f mice is reversed by P4 treatment, contrary to what is observed in PRcre/+ Mig-6f/f mice. Also, the expression of ERα, as well as its target genes Muc-1, Clca3, Ltf and Birc1, is significantly decreased in the Wnt7acre+ Mig-6f/f mice as compared to the control and PRcre/+ Mig-6f/f after P4 treatment. Concurrently, stromal Mig-6 expression is significantly increased in Wnt7acre+ Mig-6f/f mice indicating that P4-induced stromal Mig-6 can reverse the hyperplasia seen in the Wnt7acre+ Mig-6f/f mice by regulating ERα expression level. These data suggest that epithelial Mig-6 plays an important tumor suppressor role during tumorigenesis in the uterus. (Supported by NIH, R01 HD057873) 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 2197. doi:10.1158/1538-7445.AM2011-2197