Influence of AKT pathway on progesterone receptor function in endometrial cancer

AKT通路对子宫内膜癌孕激素受体功能的影响

基本信息

批准号：
8479324
负责人：
Ji-Yong Julie Kim
金额：
$ 29.65万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-04 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8479324
关键词：
1-Phosphatidylinositol 3-Kinase AKT inhibition Affect Androgen Receptor BIRC3 gene Behavior Binding Carcinoma Cell Death Cell Line ChIP-seq Chromatin Chronic Consensus Sequence Coupled DNA Data Development Diabetes Mellitus Diagnosis Disease Effectiveness Endometrial Carcinoma Endometrial Hyperplasia without Atypia Endometrial Neoplasms Endometrial adenocarcinoma Endometrium Estrogen Receptors Estrogens Exposure to Fertility Fibrous capsule of kidney Figs - dietary Fostering Gene Deletion Gene Expression Gene Expression Profiling Gene Mutation Gene Silencing Growth Hormone Antagonists Hormones Human Hypertension In Vitro Incidence Life Expectancy MDM2 gene Mediating Mus Mutate Mutation Obesity Operative Surgical Procedures PTEN gene Pathway interactions Patients Phosphorylation Phosphorylation Site Physiological Post-Translational Protein Processing Predisposition Progesterone Progesterone Receptors Progestin Therapy Progestins Proliferating Property Proteins Proto-Oncogene Proteins c-akt Recurrence Resistance Risk Factors Role Signal Pathway Technology Testing Tumor Tissue Ubiquitination Uterus Woman Xenograft procedure cancer cell cofactor combinatorial improved in vivo in vivo Model inhibitor/antagonist insight mouse model multicatalytic endopeptidase complex mutant prevent receptor receptor binding receptor expression receptor function response steroid hormone receptor subcutaneous transcription factor tumor ubiquitin-protein ligase young woman

项目摘要

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.

描述（由申请人提供）：子宫内膜癌每年影响超过 40,000 名女性。随着预期寿命的延长以及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。长期接触雌激素且缺乏相反的孕激素与子宫内膜癌高度相关。黄体酮是一种拮抗子宫内雌激素的生长促进特性的激素。黄体酮治疗已被证明可以有效预防子宫内膜癌以及控制子宫内膜的生长。然而，孕激素对患有子宫内膜癌的女性的有效性尚不清楚。黄体酮通过其受体 (PR) 发挥作用，并调节基因的表达。为了让 PR 做到这一点，它必须在特定残基处被正确磷酸化。此外，其转录功能依赖于辅助因子可用的。有趣的是，高达 80% 的子宫内膜癌携带 PTEN 突变。鉴于 PTEN 负向调节 PI3K/AKT 通路的作用，该基因失活会导致 AKT 过度激活，从而有助于增强增殖和存活。在拟议的项目中，我们将研究 PR 的翻译后修饰、其转录功能以及在过度激活 AKT 的情况下的生理作用。这将使用最新的技术来完成，使用体外和体内模型来研究肿瘤对黄体酮和 AKT 途径抑制剂的反应行为。这项研究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。