Endometrial cancer is the most frequently diagnosed malignancy of the female genital tract in the United States. Hysterectomy is typically the first line therapeutic strategy for endometrial cancer. However, there is an increasing demand for non-surgical treatments for endometrial cancer, especially for women who may encounter surgical complications as well as patients with advanced and recurrent endometrial cancer. The current alternative to surgical management of early stage endometrial neoplasia (complex hyperplasia with atypia and grade 1 cancer) is progesterone (P4) treatment, commonly via the Levonorgestrel-Releasing Intrauterine System (Mirena IUD). However, a number of women have P4 refractory disease. Resistance to P4 treatment is the major hurdle of endometrial cancer. Therefore, identifying the molecular mechanisms of P4-resistance, with the goal of identifying alternative targets for non-surgical therapies is important. Although identification of molecular mechanisms involved in the resistance to P4 is critical to enable effective and personalized therapy discovery and development, the lack of sufficient pre-clinical animal models in translational research of endometrial cancer makes further study more difficult. In this proposal, our central hypothesis is that Mig-6 loss causes endometrial cancer with P4 resistance through activation of AKT/mTOR signaling in epithelial cells and dysregulatiuon of P4 signaling in stromal cells. We will use our P4-resistant and P4-responsive mouse models. The overall objective of this project is to help improve non-surgical approaches for early stage endometrial cancer by identifying alternative targets. 1) We will identify the molecular targets altered in P4 resistance comparing the P4-responsive and resistant mouse model and 2) evaluate the combination treatment of P4 and everolimus (mTOR inhibitor) on endometrial cancer development and progression. We will identify alternative targets for non-surgical therapies for early stage endometrial cancer.