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

大多数乳腺癌表达雌激素受体α(ER-)，并且具有雌激素依赖性。在ER中- 阳性乳腺癌，ER拮抗剂减少细胞增殖和肿瘤生长。三苯氧胺()，安氏 ER-拮抗剂在乳腺癌细胞中的作用，是目前应用最广泛的辅助治疗方法 ER阳性乳腺癌。虽然疗法对大多数患者有效，但天生的抵抗力是 观察部分患者长期治疗后对耐药的发展情况 临床上相关的结果。抵抗的分子机制尚不清楚。 虽然的作用通常完全归因于ER的拮抗作用，但也观察到对乳房的敏感性 缺乏ER的癌细胞提示了作用的替代机制。我们已经证明了GPER1 通过诱导胰岛素样生长因子结合蛋白-1的表达和抑制胰岛素样生长因子结合蛋白的表达来介导对乳腺癌细胞的作用 IGF-1R依赖的细胞信号转导。此外，我们的数据表明，GPER1介导的的这种机制 ACTION抑制胰岛素样生长因子-1刺激的ER磷酸化。胰岛素样生长因子在治疗中的作用 对抗性发生发展的研究还不够深入。GPER1介导的的作用机制 在乳腺癌细胞中的作用调节胰岛素样生长因子-1R的活性，并抑制磷酸化依赖的ER信号。 为了验证这一假设，本文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在多种乳腺癌亚型中的疗效。 这些目标的完成将导致(1)明确IGFBP家庭成员在治疗期间的作用， (2)阐明GPER1介导的抑制细胞内磷酸化依赖的ER活性的机制。 以及(3)确定驱动的IGFBP依赖的分子机制 通过调节生长因子信号而产生的抗性。在完成这些目标后，我们对以下方面的知识 GPER1介导的对乳腺癌细胞作用的分子机制将显著 并探讨GPER1在耐药发展过程中作用的分子机制 要更清晰地界定。这些实验获得的数据将为理解提供新的模式 为今后的动物模型和临床研究这一常用的治疗方法提供作用。

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.