Influence of AKT pathway on progesterone receptor function in endometrial cancer

描述(申请人提供)：子宫内膜癌每年影响40,000多名妇女。随着预期寿命的增加和包括肥胖在内的关键危险因素变得更加普遍，子宫内膜癌的发病率正在上升。长期暴露于雌激素并缺乏反孕激素与子宫内膜癌有很高的相关性。黄体酮是一种荷尔蒙，它能拮抗子宫中雌激素的促生长作用。孕激素治疗已被证明在预防子宫内膜癌以及控制子宫内膜生长方面有效。然而，孕激素对患有子宫内膜癌的女性的疗效尚不清楚。孕酮通过其受体(PR)发挥作用，并调节基因的表达。为了让PR做到这一点，它必须在特定的残基上适当地磷酸化。此外，它的转录功能依赖于辅助因子 可用。有趣的是，多达80%的子宫内膜癌携带PTEN突变。鉴于PTEN负调控PI3K/AKT途径的作用，该基因的失活会导致AKT的高度激活，从而促进细胞的增殖和存活。在拟议的项目中，我们将研究PR的翻译后修饰、其转录功能以及在高度激活的AKT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激素和AKT途径抑制剂的反应。这项研究产生的信息可能有助于开发使用AKT途径的激素和抑制剂的组合疗法。

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.