The Role of GPR30 in Advanced Endometrial Cancer

雌激素是人体内的一种关键荷尔蒙，因为它调节生长、发育和 许多组织的动态平衡，包括对哺乳动物生殖和乳房功能的调节， 中枢神经系统和免疫系统、骨骼生理学和血管功能。我们的长期目标是 阐明一种新的细胞内7跨膜G蛋白偶联雌激素受体的作用 (GPR30)我们提出了与传统雌激素受体(ER)一样的功能来调节生理 对雌激素的反应性。具体的假设是，通过GPR30发出的信号调节子宫 功能与癌症的发展。我们基于我们最近观察到的GPR30 代表一个功能性的，雌激素结合的G蛋白偶联受体(GPCR)，2)GPR30激活新的 核磷脂酰肌醇信号转导途径和3)GPR30在子宫腺中特异表达 在子宫内膜癌中呈高表达。具体目标是： 1.研究GPR30对雌激素诱导的细胞活化作用的影响。我们将比较启动的细胞信号 通过GPR30和传统ER，在雌激素和雌激素类似物的刺激下，确定 临床使用的激酶抑制剂易瑞沙和拉帕替尼的疗效。 2.GPR30动物模型在子宫生物学和肿瘤发生中的作用我们将确定发展中的 GPR30在正常和肿瘤小鼠子宫中的调节。使用GPR30基因敲除小鼠，我们将 确定GPR30在子宫雌激素依赖信号转导中的作用及其调节方式 子宫内膜肿瘤的发生。 3.GPR30在子宫内膜癌中的表达我们将调查GPR30在以下方面的作用 一种新的预测中高危子宫内膜分级、分期和不良结局的生物标志物 癌症。 结合翻译性临床试验表征这种新型雌激素受体的功能 将有助于我们理解雌激素诱导的肿瘤子宫的生长和增殖， 使GPR30发展成为一种新的生物标记物和诊断和治疗的靶标 发展。

Estrogen is a critical hormone in the human body because it regulates the growth, development and homeostasis of numerous tissues, including the regulation of mammalian reproduction and breast function, the central nervous and immune systems, skeletal physiology and vascular function. Our long-term goal is to elucidate the role of a novel intracellular, 7-transmembrane spanning, G protein-coupled estrogen receptor (GPR30) that we propose functions alongside the traditional estrogen receptor (ER) to regulate physiological responsiveness to estrogen. The specific hypothesis is that signaling through GPR30 regulates uterine function and cancer development. We base this hypothesis on our recent observations that 1) GPR30 represents a functional, estrogen-binding G protein-coupled receptor (GPCR), 2) GPR30 activates novel nuclear phosphatidylinositol signaling pathways and 3) GPR30 is specifically expressed in uterine glandular epithelium and overexpressed in endometrial cancer. The specific aims are: 1. Characterize estrogen-mediated cellular activation by GPR30. We will compare cellular signaling initiated by GPR30 and traditional ERs, stimulated by estrogen as well as estrogen analogs, and determine the effects of the clinically used kinase inhibitors Iressa and Lapatinib. 2. Animal models of GPR30 function in uterine biology and neoplasia. We will determine the developmental regulation of GPR30 in the normal and neoplastic mouse uterus. Using GPR30 knockout mice, we will determine the role of GPR30 in estrogen-dependent signaling in the uterus and how this regulates endometrial tumor development. 3. Evaluation of GPR30 expression in human endometrial cancer. We will investigate the role of GPR30 as a novel biomarker predictive of grade, stage and adverse outcome in intermediate and high-risk endometrial cancer. Characterizing the functions of this novel estrogen receptor in conjunction with translational clinical trials will contribute to our understanding of estrogen-induced growth and proliferation in the neoplastic uterus, leading to the development of GPR30 as a novel biomarker and as a target for diagnostic and therapeutic development.