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G protein-coupled estrogen receptor GPER and breast carcinogenesis

G蛋白偶联雌激素受体GPER与乳腺癌发生

基本信息

批准号：
8849761
负责人：
Eric R Prossnitz
金额：
$ 31.33万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
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：
2012-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8849761
关键词：
Affect Affinity Agonist Binding Biological Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer Treatment Breast Carcinogenesis Breast Epithelial Cells Breast cancer metastasis Carcinogens Cell Survival Cessation of life Classification Coupled Dependence Development Disease Drug Targeting Drug resistance Endometrial Epithelial Cell Proliferation Estrogen Antagonists Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogen Therapy Estrogen receptor positive Estrogens Event Family Fulvestrant Future GTP-Binding Proteins Goals Growth Growth and Development function Human Human Activities Immigration Knowledge Lead Ligands Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Mediating Modeling Molecular Probes Mus Neoplasm Metastasis Normal Cell Outcome Ovarian Pharmaceutical Preparations Phase I Clinical Trials Play Prevention Process Publications RBM5 gene Receptor Signaling Research Resistance Role Science Selective Estrogen Receptor Modulators Severities Signal Transduction Tamoxifen Testing Therapeutic Therapeutic Agents Treatment Efficacy Tumor Burden Woman Work cancer initiation carcinogenesis cell transformation chemotherapeutic agent genetic manipulation in vivo inhibitor/antagonist insight malignant breast neoplasm migration mouse model neoplastic cell new therapeutic target novel novel therapeutic intervention novel therapeutics preclinical study prevent prognostic programs receptor receptor binding response screening small molecule targeted treatment tumor tumor growth

项目摘要

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.

描述（申请人提供）：雌激素及其受体是乳腺癌发生、进展、转移和治疗的关键因素。除了经典的核雌激素受体 ERα 和 ERβ 之外，7 次跨膜 G 蛋白偶联雌激素受体 GPER 现在被认为介导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剂（SERD，如氟维司群）形式的抗雌激素疗法在许多 ER 阳性乳腺癌患者中取得了巨大成功；然而，内在的和后天的抵抗力仍然是重大问题。他莫昔芬和氟维司群是 GPER 的激动剂，表明 GPER 可能在这些药物的耐药性中发挥作用。我们已经鉴定出 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。目标 1 将测试 GPER 是否介导细胞效应，包括响应雌激素、抗雌激素和 GPER 选择性配体的增殖、存活、转化和迁移。目标 2 将测试选择性靶向 GPER 活性是否会调节小鼠乳腺癌模型的癌发生和转移。目标 3 将测试 GPER 的选择性激活和抑制是否调节正常人乳腺组织和人乳腺肿瘤外植体中细胞的增殖和存活。意义：这些目标的完成将显着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性等多个方面的作用的认识，并提供深入的了解，从而确定存在高选择性拮抗剂的新治疗靶点。这种拮抗剂的进一步开发可能会产生一种治疗表达 GPER 的乳腺肿瘤的新药。