Abstract 428: The role of Mig-6 as a tumor suppressor in metastatic and recurrent endometrial cancer

Abstract

Abstract Endometrial cancer is the most common gynecologic malignancy with an estimated 63,230 new cases in 2018. Although early-stage and low grade endometrioid endometrial cancers (EEC) generally exhibit a favorable prognosis, 10-15% of tumors recur within 5 years with poor treatment outcomes and low survival rates. Therefore, there is an urgent obligation to explore the mechanism of tumor metastasis and recurrence to further elucidate the progression of EEC. Mitogen inducible gene 6 (MIG-6) plays a tumor suppressor role in endometrial cancer. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced EEC. However, how MIG-6 suppresses tumorigenesis and metastasis in EEC is unclear. We have developed a genetically engineered mouse model for metastatic and recurrent EEC that implicates coexistent Pten and Mig-6 mutations in EEC. We also added a double-fluorescent Cre reporter to our EEC mouse model to distinguish EEC from surrounding normal tissues. In Pgrcre/+Rosa26mTmG mice, the Pgr-positive uterine cells express GFP, while Pgr-negative cells express membrane-targeted tandem dimer Tomato. The ablation of both Mig-6 and Pten in the uterus (Pgrcre/+Mig-6f/fPtenf/f; Mig-6d/dPtend/d) dramatically accelerated the development of EEC compared to single ablation of either gene. Importantly, Pten mutation is not sufficient for distant metastasis, but mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. After hysterectomy at stage I of EEC, 62% of Mig-6d/dPtend/d mice (5/8) developed recurrence of EEC in the abdomen and lung. Cholesterol metabolism plays a significant role in cancer metastasis, and Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis. The ingenuity pathway analysis revealed that cholesterol biosynthesis was the most significantly changed pathway in the endometrial hyperplasia from 2-week-old Mig-6d/dPtend/d mice compared with Ptend/d mice. We found 67 and 18 significantly increased or decreased transcripts, respectively, that are related cholesterol biosynthesis. HMG-coA reductase inhibitors, commonly known as statins, account for the great majority of cholesterol-lowering drug use. However, little is known about the association between statin use and incidence of most types of cancers. To determine the effect of statins on tumorigenesis of EEC in Mig-6d/dPtend/d mice, the mutant mice were treated with atorvastatin (10mg/kg/day oral administration) or vehicle for 2 months. Treatment with statins significantly reduced development and progression of EEC in Mig-6d/dPtend/d mice compared to the vehicle group. Our results demonstrate that Mig-6 suppresses metastasis and recurrence in EEC with Pten mutation by inhibiting cholesterol biosynthesis. Research reported in this publication was supported by The Mary Kay Foundation 2019 research grant. Citation Format: Tae Hoon Kim, Ryan M. Marquardt, Russell R. Broaddus, Jae-Wook Jeong. The role of Mig-6 as a tumor suppressor in metastatic and recurrent endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 428.