Abstract 2069: Stromal-epithelial crosstalk of Mig-6 has an important role for tumor suppression via progesterone in endometrial cancer

Abstract

Abstract Endometrial cancer is the most common malignancy of the female genital tract. This disease is commonly caused by an imbalance of progesterone (P4) and estrogen (E2) action that E2 stimulates proliferation of uterine epithelial cells while P4 is inhibitory to estrogen-mediated proliferation of the epithelium. Endometrial hyperplasia is also associated with endometrial cancer, which is a proliferative process in epithelium by E2. Responsiveness of progesterone is required to treat endometrial cancer and preserve the fertility of patients. Furthermore, PR expression in the uteri of patients with endometrial cancer has been used as an indicator for a first-rate prognosis. However, more than 30% of patients do not respond to progesterone treatment as a result of progesterone resistance and the mechanism of progesterone resistance is still unknown. Thus, identifying the mechanism of progesterone in endometrial cancer is essential to improve the therapy of this disease. Mitogen-inducible gene 6 (Mig-6) is an important mediator of progesterone receptor (PR) action in the murine uterus. As P4 achieves the inhibition of proliferation by coordinating stromal-epithelial cross-talk, we generated a mouse model in which we specifically ablate epithelial endometrial Mig-6 using Sprr2f-cre mice (Sprr2fcre+ Mig-6f/f) to understand the role of epithelial Mig-6 in the uterus. Sprr2fcre+ Mig-6f/f mice displayed endometrial hyperplasia upon 10 weeks of age and develop endometrial cancer by E2 treatment for 3 months. Interestingly, the hyperplasia exhibited by Sprr2fcre+ Mig-6f/f mice was prevented by P4 treatment for 1 week in morphological and histological analysis. Proliferation decreased in the glandular epithelium of Sprr2fcre+ Mig-6f/f mice by P4, and apoptotic signal was also reduced. The expressions of stromal PR and its target genes were induced in Sprr2fcre+ Mig-6f/f mice after P4 treatment, indicating that P4-induced stromal Mig-6 can prevent the hyperplasia via regulating steroid hormonal signaling. This study suggested that stromal-epithelial communication of Mig-6 is critical in tumor suppressor function via regulating steroid hormonal signaling by progesterone. (This work was supported by American Cancer Society Research Grant, RSG-12-084-01-TBG to J.W.J.) Citation Format: Tae Hoon Kim, Byung Gak Kim, Jung-Yoon Yoo, Jae Hee Lee, Diego H. Castrillon, Jae-Wook Jeong. Stromal-epithelial crosstalk of Mig-6 has an important role for tumor suppression via progesterone in endometrial cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2069. doi:10.1158/1538-7445.AM2015-2069