GPER1-dependent regulation of IGF-1R in tamoxifen treated breast cancer cells

他莫昔芬处理的乳腺癌细胞中 GPER1 依赖性 IGF-1R 调节

• 批准号: 10321205
• 负责人: Kevin D. Houston
• 金额: $ 37万
• 依托单位: NEW MEXICO STATE UNIVERSITY LAS CRUCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321205
• 关键词: Adjuvant Therapy; Agonist; Animal Model; Basic Science; Breast Cancer Cell; Breast Cancer cell line; Cell Cycle Regulation; Cell Proliferation; Cells; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Diagnosis; Dose; ESR1 gene; Epidermal Growth Factor Receptor; Estrogen Nuclear Receptor; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Family member; Fulvestrant; Future; GPER gene; Gene Expression; Genes; Genetic Transcription; Goals; Growth Factor; IGFBP1 gene; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Knowledge; Laboratories; Ligands; Link; Mediating; Membrane; Modeling; Molecular; Outcome; Patients; Phosphorylation; Play; Protocols documentation; Publishing; Receptor Activation; Receptor Signaling; Regulation; Research; Resistance; Role; Signal Transduction; Small Interfering RNA; Tamoxifen; Testing; Therapeutic; Therapeutic Uses; Transfection; United States National Institutes of Health; Work; antagonist; base; breast cancer progression; cancer subtypes; clinically relevant; experimental study; imprint; knock-down; malignant breast neoplasm; mutant; promoter; receptor expression; therapeutic target; therapy development; tumor growth

The majority of breast cancers express estrogen receptor alpha (ER) and are estrogen-dependent. In ER- positive breast cancer, ER antagonists decrease cell proliferation and tumor growth. Tamoxifen (Tam), an ER antagonist in breast cancer cells, is the most widely used adjuvant therapy for patients diagnosed with ER-positive breast cancer. While Tam treatment is effective for most patients, innate Tam resistance is observed in some patients and the development of Tam resistance after long-term treatment remains a clinically relevant outcome. The molecular mechanisms that underlie Tam resistance are not well understood. While Tam action is often attributed entirely to ER antagonism, Tam sensitivity has been observed in breast cancer cells that lack ER suggesting alternative mechanisms of Tam action. We have shown that GPER1 mediates Tam action in breast cancer cells via induction of IGFBP-1 expression and subsequent inhibition of IGF-1R-dependent cell signaling. Additionally, our data indicate that this GPER1-mediated mechanism of Tam action inhibits IGF-1-stimulated ER phosphorylation. The role of IGFBPs during Tam treatment and the development of Tam resistance has not been adequately studied. GPER1-mediated mechanisms of Tam action in breast cancer cells modulate IGF-1R activity and inhibit phosphorylation-dependent ER signaling. To test this hypothesis, three independent Aims are proposed. Included in all three Aims are experiments utilizing a panel of breast cancer cell lines to model Tam efficacy in multiple breast cancer subtypes. Completion of these aims will result in (1) Defining the role of IGFBP family members during Tam treatment, (2) Elucidating GPER1-mediated mechanisms that inhibit phosphorylation-dependent ER activity in Tam- treated breast cancer cells, and (3) Determine the IGFBP-dependent molecular mechanisms that drive Tam resistance via modulation of growth factor signaling. Upon completion of these Aims, our knowledge regarding the molecular mechanisms of GPER1-mediated Tam action in breast cancer cells will be significantly increased and the molecular mechanisms of the role of GPER1 during the development of Tam resistance will be more clearly defined. Data obtained from these experiments will provide new models of understanding Tam action for future animal model and clinical studies of this commonly used therapeutic.

大多数乳腺癌表达雌激素受体α（ER β），并且是雌激素依赖性的。在急诊室， 在乳腺癌阳性的情况下，ER β拮抗剂降低细胞增殖和肿瘤生长。他莫昔芬（Tam），一种 乳腺癌细胞中的ER β拮抗剂，是诊断为乳腺癌的患者最广泛使用的辅助治疗。 ER β阳性乳腺癌。虽然Tam治疗对大多数患者有效，但先天性Tam抵抗 在一些患者中观察到，长期治疗后Tam耐药性的发展仍然是一个问题。 临床相关结果。Tam抗性的分子机制尚未完全了解。 虽然Tam的作用通常完全归因于ER β拮抗作用，但在乳腺癌中观察到Tam敏感性。 缺乏ER β的癌细胞表明Tam作用的替代机制。我们已经证明，GPER 1 在乳腺癌细胞中通过诱导IGFBP-1表达和随后抑制IGFBP-1表达介导Tam作用。 IGF-1 R依赖的细胞信号传导。此外，我们的数据表明，这种GPER 1介导的Tam机制， 作用抑制IGF-1刺激的ER β磷酸化。IGFBPs在Tam治疗过程中的作用以及 Tam抗性的发展尚未得到充分研究。GPER 1介导的Tam机制 在乳腺癌细胞中的作用调节IGF-1 R活性并抑制磷酸化依赖性ER β信号传导。 为了检验这一假设，提出了三个独立的目标。这三个目标都包括实验 利用一组乳腺癌细胞系来模拟Tam在多种乳腺癌亚型中的功效。 这些目标的完成将导致（1）确定IGFBP家族成员在Tam治疗期间的作用， (2)阐明GPER 1介导的抑制Tam-2细胞中磷酸化依赖性ER β活性的机制。 治疗的乳腺癌细胞，和（3）确定IGFBP依赖的分子机制，驱动Tam 通过调节生长因子信号传导的抗性。在完成这些目标后，我们对 乳腺癌细胞中GPER 1介导的Tam作用的分子机制将显着 GPER 1在Tam抗性发展过程中的作用的分子机制将 更明确地定义。从这些实验中获得的数据将为理解Tam提供新的模型 为今后的动物模型和临床研究这一常用的治疗行动。