The Role of GPR30 in Advanced Endometrial Cancer

描述（由申请人提供）：雌激素是人体中的一种关键激素，因为它调节许多组织的生长，发育和稳态，包括哺乳动物生殖和乳房功能，中枢神经和免疫系统，骨骼生理和血管功能的调节。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（GPR30）的作用，我们提出它与传统的雌激素受体（ER）一起调节对雌激素的生理反应。具体的假设是通过GPR30信号调节子宫功能和癌症的发生。我们的假设基于我们最近的观察：1)GPR30是一种功能性的雌激素结合G蛋白偶联受体（GPCR）， 2) GPR30激活新的核磷脂酰肌醇信号通路，3)GPR30在子宫腺上皮中特异性表达，并在子宫内膜癌中过表达。具体目标是：1。用GPR30表征雌激素介导的细胞活化。我们将比较GPR30和传统er在雌激素和雌激素类似物刺激下启动的细胞信号，并确定临床使用的激酶抑制剂易瑞沙和拉帕替尼的效果。GPR30在子宫生物学和肿瘤发育中的作用的动物模型。我们将确定GPR30在正常和肿瘤小鼠子宫中的发育调控作用。使用GPR30敲除小鼠，我们将确定GPR30在子宫雌激素依赖信号传导中的作用，以及它如何调节子宫内膜肿瘤的发展。3. GPR30在人子宫内膜癌组织中的表达。我们将研究GPR30作为一种预测中高危子宫内膜癌分级、分期和不良结局的新型生物标志物的作用。将这种新型雌激素受体的功能与转化临床试验相结合，将有助于我们了解雌激素诱导的肿瘤子宫生长和增殖，从而使GPR30成为一种新的生物标志物，并作为诊断和治疗的靶点。

DESCRIPTION (provided by applicant): 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.