Endometrial cancer affects more than 40,000 women per year. The incidence of endometrial cancer is rising as life expectancy increases and as key risk factors, including obesity, becomes more prevalent. Chronic exposure to estrogen with a lack of opposing progesterone is highly associated with endometrial carcinoma. Progesterone is a hormone that antagonizes the growth-promoting properties of estrogen in the uterus. Progesterone therapy has been shown to be effective in preventing endometrial cancer as well as controlling growth of the endometrium. However, the effectiveness of progestins for women with endometrial cancer is less clear. Progesterone functions through its receptor (PR), and regulates the expression of genes. For PR to do this, it must be properly phosphorylated at specific residues. Furthermore, its transcriptional function is dependent on the cofactors that are available. Interestingly, up to 80% of endometrial cancers carry a PTEN mutation. Given the role of PTEN to negatively regulate the PI3K/AKT pathway, inactivation of this gene results in hyper activated AKT, which contributes to enhanced proliferation and survival. In the proposed project, we will study the post translational modification of PR, its transcriptional function and the physiological role in the context of hyper activated AKT. This will be done using the most current technologies, using in vitro and in vivo models to study tumor behavior in response to progesterone and inhibitors of the AKT pathway. The information generated from this study may contribute towards the development of combinatorial therapies using hormones and inhibitors of the AKT pathway.