G protein-coupled estrogen receptor GPER and breast carcinogenesis

说明(申请人提供)：雌激素及其受体是乳腺癌发生、发展、转移和治疗的关键因素。除了经典的核雌激素受体ERα和ERβ外，7-跨膜G蛋白偶联的雌激素受体GPER现在被认为介导了许多与雌激素作用相关的快速信号事件。选择性雌激素受体调节剂(SERM，如他莫昔芬)和选择性雌激素受体下调调节剂(SERD，如Fulvestrant)形式的抗雌激素治疗在许多ER阳性的乳腺癌患者中非常成功；然而，内在和获得性耐药仍然是重要的问题。他莫昔芬和Fulvestrant是GPER的激动剂，提示GPER可能在这些药物的耐药性中起作用。我们已经确定了GPER的选择性激动剂和拮抗剂，这将使我们能够检验GPER在乳腺癌发生和治疗效果中发挥重要作用的假设。目的1将测试GPER是否在雌激素、抗雌激素和GPER选择性配体的作用下介导细胞的增殖、存活、转化和迁移。目的2将在乳腺癌小鼠模型中测试选择性靶向GPER活性是否调节肿瘤的发生和转移。目的研究选择性激活和抑制GPER是否调节正常乳腺组织和人乳腺肿瘤外植体细胞的增殖和存活。意义：这些目标的完成将大大提高我们对新型雌激素受体GPER在乳腺癌从起始到转移和耐药等多个方面的作用的了解和洞察，从而确定一个新的治疗靶点，为其提供高选择性拮抗剂。这种拮抗剂的进一步开发可能会导致一种治疗GPER表达的乳腺肿瘤的新药。

DESCRIPTION (provided by applicant): Estrogen and its receptors are critical factors in the development, progression, metastasis and treatment of breast cancer. In addition to the classical nuclear estrogen receptors, ERalpha and ERbeta, the 7-transmembrane G protein-coupled estrogen receptor GPER is now recognized as mediating many of the rapid signaling events associated with estrogen action. Anti-estrogen therapies in the form of selective estrogen receptor modulators (SERMs, such as tamoxifen) and selective estrogen receptor down regulators (SERDs, such as Fulvestrant) have been highly successful in many ER-positive breast cancer patients; however, intrinsic and acquired resistance remains significant problems. Tamoxifen and Fulvestrant are agonists of GPER, suggesting that GPER may play a role in resistance to these drugs. We have identified both a selective agonist and antagonists of GPER that will allow us to test the hypothesis that GPER plays an important role in breast carcinogenesis and treatment efficacy. Aim 1 will test whether GPER mediates cellular effects including proliferation, survival, transformation and migration in response to estrogen, anti-estrogens and GPER-selective ligands. Aim 2 will test whether selective targeting of GPER activity modulates carcinogenesis and metastasis in a murine model of breast cancer. Aim 3 will test whether selective activation and inhibition of GPER regulates proliferation and survival of cells in normal human breast tissue and human breast tumor explants. Significance: Completion of these aims will significantly advance our knowledge of and provide insight into the role of the novel estrogen receptor GPER in multiple aspects of breast cancer, from initiation to metastasis and drug resistance resulting in the identification of a novel therapeutic target for which highly selective antagonists exist. Further development of this antagonist could lead to a new drug for the treatment of GPER-expressing breast tumors.