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

• 批准号: 10472699
• 负责人: Eric R Prossnitz
• 金额: $ 34.69万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 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/10472699
• 关键词: Affinity; Aftercare; Agonist; Apoptosis; 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; Inhibition of Cell Proliferation; Kinetics; Knowledge; Lead; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mouse Mammary Tumor Virus; Mus; Mutation; Names; Nature; Outcome; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Physiology; Postmenopause; RBM5 gene; Recurrence; Recurrent disease; Regimen; Reporting; Resistance; Resistance development; Risk; Role; Selective Estrogen Receptor Modulators; Signal Transduction; Tamoxifen; Testing; Therapeutic Agents; Thromboembolism; Time; Translations; Tumor Suppressor Proteins; Woman; antagonist; cancer recurrence; cross reactivity; experience; genetic approach; human disease; improved; in vivo; malignant breast neoplasm; mammary epithelium; mouse model; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; prevent; refractory cancer; side effect; targeted treatment; therapy resistant; tool; transcription factor

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)调节剂和下调调节剂(SERM和SERD)，也 被认为是抗激素)挽救了数百万ER阳性乳房妇女的生命 癌症。不幸的是，其中大约三分之一的女性表现出内在的抵抗力 这些靶向治疗，而接受抗激素治疗的女性将出现类似的比例 随着时间的推移，耐药性会导致更具侵袭性的癌症复发。SERM和 SERD抑制经典的核雌激素受体α，导致细胞抑制 扩散和生存。相比之下，我们的结果表明，这些药物激活了 7-跨膜G蛋白偶联雌激素受体GPER，导致 刺激促生存的PI3K/Akt轴。此外，我们最近的研究表明， 这可能通过FOXO_3促凋亡转录的磷酸化和失活来实现。 因素。我们已经确定了一系列新的化合物，这些化合物对任何一种都表现出很强的选择性 ERα或GPER。通过将这些药理学方法与遗传方法相结合，我们 假设获得性抗激素抵抗涉及GPER的激活，结果 在FOXO_3的失活中。我们建议通过以下具体目标来检验这一假设： 目标1将测试GPER是否介导获得性乳腺癌对SERM和SERD的耐药性。 Aim 2将测试FOXO3的失活是否代表着增强肿瘤细胞的关键步骤 在面对ERα抑制时存活。目标3将采用自发乳房的小鼠模型 以测试阻断GPER活性是否与他莫昔芬联合治疗，或 或者用新药选择性地抑制ERα，防止获得性耐药。 意义：完成这些目标将极大地提高我们对 新型雌激素受体GPER在乳腺癌获得性抗激素抵抗中的作用。识别 联合应用GPER作为乳腺癌获得性抗激素耐药的新介体 随着使用新的高选择性配体在这一提案中进行评估，可能会导致显著的 15万名被诊断为ER阳性乳腺癌的妇女的预后改善 年。