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：
10689300
负责人：
Eric R Prossnitz
金额：
$ 19.11万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10689300
关键词：
Affinity Aftercare Agonist Apoptotic Aromatase Inhibitors Binding Biological Breast Cancer Treatment Breast Carcinogenesis CRISPR/Cas technology Cell Death Cell Proliferation Cell Survival Collection Development Diagnosis Drug resistance Effectiveness Endometrial Carcinoma Estrogen Antagonists Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptors Estrogen receptor positive Estrogens FOXO3A gene Frequencies GPER gene Genetic Germ Cells Goals Hormones In Vitro Induction of Apoptosis Inhibition of Cell Proliferation Kinetics Knowledge Lead Ligands Malignant Neoplasms Mediating Mediator Membrane Modeling Mouse Mammary Tumor Virus Mus Mutation Names Nature Outcome PIK3CG gene Pharmaceutical Preparations Phosphorylation Physiology Postmenopause Proliferating RBM5 gene Recurrence Recurrent Malignant Neoplasm Recurrent disease Regimen Reporting Resistance Resistance development Risk Role Selective Estrogen Receptor Modulators Signal Transduction Tamoxifen Testing Therapeutic Agents Thromboembolism Time Tumor Suppressor Proteins Woman antagonist cancer recurrence constitutive expression cross reactivity experience genetic approach hormone resistance hormone therapy human disease improved in vivo malignant breast neoplasm mammary epithelium mouse model mutant neoplastic cell novel novel therapeutic intervention novel therapeutics pharmacologic polyoma middle tumor antigen prevent refractory cancer side effect targeted treatment tool transcription factor translational potential

项目摘要

Selective estrogen receptor (ER) modulators and downregulators (SERMs and SERDs, also refereed to as anti-hormones) have saved the lives of millions of women with ER-positive breast cancer. Unfortunately, approximately one-third of these women display intrinsic resistance to these targeted therapies, while a similar fraction of women treated with anti-hormones will develop resistance over time, resulting in recurrences of often more aggressive cancers. SERMs and SERDs inhibit the classical nuclear estrogen receptor ERα, leading to the inhibition of cell proliferation and survival. In contrast, our results have shown that these same drugs activate the 7-transmembrane spanning G protein-coupled estrogen receptor GPER, resulting in the stimulation of the pro-survival PI3K/Akt axis. Furthermore, our recent studies have suggested that this may occur through phosphorylation and inactivation of the FOXO3 pro-apoptotic transcription factor. We have identified a collection of novel compounds that display strong selectivity for either ERα or GPER. By combining these pharmacological approaches with genetic approaches, we hypothesize that acquired resistance to anti-hormones involves their activation of GPER, resulting in the inactivation of FOXO3. We propose to test this hypothesis with the following specific aims: Aim 1 will test whether GPER mediates acquired breast cancer resistance to SERMs and SERDs. Aim 2 will test whether the inactivation of FOXO3 represents a critical step in enhancing tumor cell survival in the face of ERα inhibition. Aim 3 will employ a murine model of spontaneous breast cancer to test whether blocking GPER activity in combination with tamoxifen treatment, or alternatively selectively inhibiting ERα with novel drugs, prevents acquired resistance. Significance: Completion of these aims will significantly advance our knowledge of the role of the novel estrogen receptor GPER in acquired anti-hormone resistance in breast cancer. Identifying GPER as a novel mediator in acquired anti-hormone resistance in breast cancer in combination with the use novel highly selective ligands to be evaluated in this proposal could lead to significant improvements in outcome for the150,000 women diagnosed with ER-positive breast cancer each year.

选择性雌激素受体（ER）调节剂和下调器（Serm and Serds，也是被称为抗激素）已挽救了数百万具有ER阳性乳房的女性的生命癌症。不幸的是，这些女性中约有三分之一表现出对这些有针对性的疗法，而用抗激素治疗的女性类似的疗法将发展随着时间的流逝，阻力通常会带来更具侵略性的癌症的回报。 Serms和 SERD抑制经典的核雌激素受体ERα，导致细胞抑制增殖和生存。相反，我们的结果表明，这些相同的药物激活了 7跨膜跨越G蛋白偶联的雌激素受体GPER，导致刺激生存PI3K/AKT轴的刺激。此外，我们最近的研究表明这可能通过FOXO3促凋亡转录的磷酸化和灭活发生因素。我们已经确定了一系列新型化合物，这些化合物表现出强烈的选择性 ERα或GPER。通过将这些药物方法与遗传方法相结合，我们假设获得对抗激素的耐药性涉及其激活GPER，从而在Foxo3的失活中。我们建议以以下特定目的检验这一假设： AIM 1将测试GPER是否介导获得的乳腺癌对Serm和Serds的抗性。 AIM 2将测试FOXO3的灭活是否代表增强肿瘤细胞的关键步骤面对ERα抑制作用。 AIM 3将采用赞助乳房的鼠模型癌症测试是否与他莫昔芬治疗联合阻断GPER活性，还是或者，用新药物选择性地抑制ERα可防止获得的抗药性。意义：这些目标的完成将大大提高我们对在获得乳腺癌中获得的抗激素耐药性中，新型的雌激素受体GPER。识别 GPE是乳腺癌中获得的抗激素耐药性的新型调解人使用新颖的高度选择性配体在此提案中进行评估可能会导致重要改善被诊断为ER阳性乳腺癌的15万名女性的结果改善年。

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Female Sex Hormone Receptor Profiling in Uterine Adenosarcomas.

DOI：
10.1097/igc.0000000000001183
发表时间：
2018-03
期刊：
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
影响因子：
0
作者：
Marcus JZ;Klobocista M;Karabakhtsian RG;Prossnitz E;Goldberg GL;Huang GS
通讯作者：
Huang GS

Estrogen receptor quantitative measures and breast cancer survival.

DOI：
10.1007/s10549-017-4439-6
发表时间：
2017-12
期刊：
Breast cancer research and treatment
影响因子：
3.8
作者：
Hill DA;Barry M;Wiggins C;Nibbe A;Royce M;Prossnitz E;Lomo L
通讯作者：
Lomo L

Emerging roles of GPER in diabetes and atherosclerosis.

DOI：
10.1016/j.tem.2015.02.003
发表时间：
2015-04
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
0
作者：
Barton M;Prossnitz ER
通讯作者：
Prossnitz ER

Targeted Phage Display-based Pulmonary Vaccination in Mice and Non-human Primates.

DOI：
10.1016/j.medj.2020.10.005
发表时间：
2021-03-12
期刊：
Med (New York, N.Y.)
影响因子：
0
作者：
Staquicini DI;Barbu EM;Zemans RL;Dray BK;Staquicini FI;Dogra P;Cardó-Vila M;Miranti CK;Baze WB;Villa LL;Kalil J;Sharma G;Prossnitz ER;Wang Z;Cristini V;Sidman RL;Berman AR;Panettieri RA Jr;Tuder RM;Pasqualini R;Arap W
通讯作者：
Arap W

Role of GPER in estrogen-dependent nitric oxide formation and vasodilation.