Extranuclear estrogen receptor actions on endometrial cancer cell proliferation

描述(申请人提供)：子宫内膜癌是最常见的浸润性妇科癌症，在美国女性中排名第四。预测表明，2005年将有40,100例新病例和估计7,000例死亡。雌激素(通过雌激素受体)在子宫内膜提供主要的增殖信号，并控制许多组织的增殖和分化等关键细胞过程，包括子宫、乳房、肝脏和大脑。雌激素受体历来被认为是一种配体依赖的转录因子，通过基因调控发挥作用。最近的观察表明，雌激素和其他类固醇激素引起细胞信号转导通路的快速激活，这些被称为核外作用。这些研究的总体目标是确定雌激素快速激活细胞质信号通路的机制，并研究这些通路在子宫内膜癌细胞增殖中的功能作用。这将通过确定子宫内膜癌细胞的生长曲线来实现，这些细胞被设计为只表达转录上不活跃的雌激素受体，以响应雌激素。生化分析和药物抑制将被用来确定雌激素依赖的信号通路对子宫内膜癌细胞增殖的贡献。雌激素受体激活丝裂原活化(MAP)激酶、PI3激酶、蛋白激酶C和其他信号分子的机制将侧重于剖析迅速发生在质膜上的蛋白质与蛋白质之间的相互作用，以响应雌激素。我们将研究PTEN在负性调节核外雌激素受体作用和随后的子宫内膜癌细胞增殖中的作用。I型子宫内膜癌被认为主要是一种非对抗性雌激素引起的疾病。肥胖促进了长期的雌激素环境，并与子宫内膜癌发病率增加20倍相关；因此，社会肥胖症的增加可能会导致子宫内膜癌的增加。拟议的研究将为雌激素受体作用的子集提供重要的见解，这些作用可能为内分泌治疗提供潜在的靶点。 公共卫生相关性：子宫内膜癌是最常见的浸润性妇科癌症，每年导致7500人死亡。子宫内膜癌是由慢性雌激素刺激引起的。肥胖率上升、月经初潮早、生育晚和经期延长都会导致终生接触雌激素的增加，因此预计会导致子宫内膜癌发病率的急剧增加。了解雌激素受体作用的新机制可能为内分泌治疗提供新的靶点。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common invasive gynecological cancer and the fourth most common cancer in women in the US. Projections indicate that there will be 40,100 new cases and an estimated 7000 deaths in 2005. Estrogen (through the estrogen receptor) provides the primary proliferative signal in the endometrium and controls critical cellular processes such as proliferation and differentiation in many tissues including uterus, breast, liver, brain. The estrogen receptor has historically been thought of as a ligand-dependent transcription factor that exerts its effects by gene regulation. Recent observations suggest that the estrogen and other steroid hormones elicit rapid activation of cellular signal transduction pathways these are termed extranuclear actions. The general objectives of these studies are to define the mechanisms by which estrogen rapidly activates cytoplasmic signaling pathways, and to examine the functional role of these pathways in endometrial cancer cell proliferation. This will be accomplished by determining growth profiles of endometrial cancer cells engineered to express only transcriptionally inactive estrogen receptor in response to estrogen. Biochemical assays and pharmacological inhibitors will be employed to determine the contribution of estrogen dependent signaling pathways to endometrial cancer cell proliferation. The mechanisms by which the estrogen receptor activates mitogen activated (MAP) kinases, PI3 kinase, protein kinase C and other signaling molecules will emphasize dissection of the protein-protein interactions that occur rapidly at the plasma membrane in response to estrogen. The role of PTEN in negatively regulating extranuclear estrogen receptor actions and consequent endometrial cancer cell proliferation will be investigated. Type 1 endometrial cancer is considered to be primarily a disease of unopposed estrogen. Obesity promotes a chronic estrogen environment and correlates with a 20 fold increase in the incidence of endometrial cancer; therefore, the increase in societal obesity will likely lead to and increase in endometrial cancer. The proposed studies will offer important insights into a subset of estrogen receptor actions that may provide potential targets for endocrine therapies. PUBLIC HEALTH RELEVANCE: Endometrial cancer is the most common invasive gynecological cancer and causes 7500 deaths per year. Endometrial cancer is caused by chronic estrogen stimulation. Rising obesity rates, early menarche, later child birth and extended years of menstuation all contribute to increased lifetime exposure to estrogen, and therefore are predicted to lead to dramatic increases in endometrial cancer incidence. Understanding novel mechanisms of estrogen receptor action may provide new targets for endocrine therapies.