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

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

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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（由申请人提供）：雌激素及其受体是乳腺癌发育，进展，转移和治疗的关键因素。除了经典的核雌激素受体，Eralpha和Erbeta外，现在被认为是介导与雌激素作用相关的许多快速信号事件的7跨膜G蛋白偶联雌激素受体GPER。在许多ER阳性乳腺癌患者中，以选择性雌激素受体调节剂（SERMS，例如他莫昔芬）和选择性雌激素受体下调调节剂（SERDS）的抗雌激素疗法（SERDS）和选择性雌激素受体下调的疗法；但是，内在和获得的抵抗仍然是重大问题。他莫昔芬和富伏者是GPER的激动剂，这表明GPER可能在对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功效中起重要作用的假设。 AIM 1将测试GPER是否介导了对雌激素，抗雌激素和GPER选择配体的响应，包括增殖，存活，转化和迁移。 AIM 2将测试在乳腺癌的鼠模型中，选择性靶向GPER活性是否会调节癌变和转移。 AIM 3将测试选择性激活和GPER的抑制是否可以调节正常人乳腺组织和人类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乳腺癌的新雌激素受体GPER在乳腺癌多个方面的作用，从开始到转移和耐药性，从而鉴定出一种新型的治疗靶标的，从而识别出高度选择性拮抗剂。该拮抗剂的进一步发展可能导致一种新药物来治疗表达GPER的乳腺肿瘤。