Influence of AKT pathway on progesterone receptor function in endometrial cancer

描述（由申请人提供）：子宫内膜癌每年影响超过40,000名妇女。随着预期寿命的延长，以及肥胖等主要风险因素变得更加普遍，子宫内膜癌的发病率正在上升。长期暴露于雌激素而缺乏相反的黄体酮与子宫内膜癌高度相关。黄体酮是一种激素，可以对抗子宫内雌激素的促生长特性。黄体酮治疗已被证明是有效的预防子宫内膜癌以及控制子宫内膜的生长。然而，孕激素治疗子宫内膜癌的有效性尚不清楚。黄体酮通过其受体（PR）发挥作用，调节基因的表达。PR要做到这一点，它必须在特定残基上被适当磷酸化。此外，它的转录功能依赖于辅助因子

DESCRIPTION (provided by applicant): 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.