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。子宫内膜癌的发病率随着预期寿命的增加和包括肥胖在内的关键风险因素变得更加普遍而上升。长期暴露于雌激素而缺乏相反的孕激素与子宫内膜癌高度相关。孕激素是一种激素，拮抗子宫内雌激素的促生长特性。已证明，预后疗法在预防子宫内膜癌以及控制子宫内膜生长方面是有效的。然而，孕激素对子宫内膜癌患者的有效性尚不清楚。孕激素通过其受体（PR）发挥作用，并调节基因的表达。PR要做到这一点，它必须在特定的残基适当磷酸化。此外，它的转录功能依赖于辅因子， available.有趣的是，高达80%的子宫内膜癌携带PTEN突变。考虑到PTEN负调节PI 3 K/AKT通路的作用，该基因的失活导致AKT过度活化，这有助于增强增殖和存活。在这个项目中，我们将研究PR的翻译后修饰，它的转录功能和在超激活AKT的背景下的生理作用。这将使用最新的技术，使用体外和体内模型来研究肿瘤对孕酮和AKT通路抑制剂的反应。从这项研究中产生的信息可能有助于开发使用激素和AKT途径抑制剂的组合疗法。

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.