Rescue chemotherapy is usually the preferred treatment for patients with advanced estrogen receptor-positive (ER+) breast cancer with endocrinotherapy resistance. However, these patients often simultaneously show a poor response to cytotoxic drugs, and thus the detailed mechanism of this resistance needs to be further investigated. Our previous research indicated that the G-protein-coupled estrogen receptor (GPER) is a novel mediator of the development of multidrug resistance, including resistance to both endocrinotherapy and chemotherapy, and ATP binding cassette subfamily G member 2 (ABCG2) has been identified as an engine that confers cancer cells with chemoresistance by expelling xenobiotics and chemotherapeutics. Here, we are the first to show that the expression levels of GPER and ABCG2 are markedly increased in tamoxifen-resistant ER + metastases compared to the corresponding primary tumors. A plasma membrane expression pattern of GPER and ABCG2 was observed in patients with metastases. Furthermore, both ER modulator tamoxifen, GPER-specific agonist G1 and pure ER antagonist ICI 182,780 significantly enhanced ABCG2 expression in tamoxifen-resistant breast cancer cells (MCF-7R) but not in tamoxifen-sensitive cells (MCF-7). The activated downstream GPER/EGFR/ERK and GPER/EGFR/AKT signaling pathways were responsible for regulating the expression and cell membrane localization of ABCG2, respectively, in MCF-7R cells. Interestingly, the above phenomenon could be alleviated by inhibitors of both the indicated signaling pathways and by knockdown of GPER in MCF-7R cells. More importantly, the tamoxifen-induced GPER/ABCG2 signaling axis was shown to play a pivotal role in the development of chemotherapy (doxorubicin) resistance both in vitro and in vivo. The clinical data further revealed that tamoxifen-resistant patients with high GPER/ABCG2 signaling activation had poor progression-free survival (PFS) when given rescue anthracycline chemotherapy. Therefore, our data provide novel insights into GPER-mediated chemoresistance and provide a rationale for the GPER/ABCG2 signaling axis being a promising target for reversing chemoresistance in patients with advanced ER + tamoxifen-resistant breast cancer.

中文翻译：

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GPER通过调节ABCG2表达和在他莫昔芬耐药乳腺癌细胞中的定位来介导降低的化学敏感性。

对于患有内分泌治疗耐药性的晚期雌激素受体阳性（ER +）乳腺癌患者，抢救化疗通常是首选治疗方法。但是，这些患者通常同时显示出对细胞毒性药物的不良反应，因此需要进一步研究这种耐药性的详细机制。我们先前的研究表明，G蛋白偶联雌激素受体（GPER）是多药耐药性发展的新型介质，包括对内分泌疗法和化学疗法的耐药性，并且已确定ATP结合盒亚家族G成员2（ABCG2）为通过排出异种生物和化学疗法使癌细胞具有化学抗性的引擎。这里，我们是第一个证明与他原发性肿瘤相比，他莫昔芬耐药的ER +转移灶中GPER和ABCG2的表达水平显着增加。在转移患者中观察到GPER和ABCG2的质膜表达模式。此外，ER调节剂他莫昔芬，GPER特异性激动剂G1和纯ER拮抗剂ICI 182,780均显着增强了他莫昔芬耐药性乳腺癌细胞（MCF-7R）中的ABCG2表达，但在他莫昔芬敏感性细胞（MCF-7）中却未增强。激活的下游GPER / EGFR / ERK和GPER / EGFR / AKT信号通路分别负责调节MCF-7R细胞中ABCG2的表达和细胞膜定位。有趣的是 上述现象可以通过既定信号通路的抑制剂和MCF-7R细胞中GPER的抑制来缓解。更重要的是，他莫昔芬诱导的GPER / ABCG2信号转导轴在体外和体内对化疗（阿霉素）耐药性的发展中起着关键作用。临床数据进一步表明，接受抢救蒽环类药物化疗时，具有高GPER / ABCG2信号激活作用的他莫昔芬耐药患者的无进展生存期（PFS）较差。因此，我们的数据为GPER介导的化学耐药性提供了新颖的见解，并为GPER / ABCG2信号轴成为晚期ER +他莫昔芬耐药性乳腺癌患者的化学耐药性逆转提供了有希望的靶点。他莫昔芬诱导的GPER / ABCG2信号转导轴在体外和体内对化疗（阿霉素）耐药性的发展中起着关键作用。临床数据进一步表明，接受抢救蒽环类药物化疗时，具有高GPER / ABCG2信号激活作用的他莫昔芬耐药患者的无进展生存期（PFS）较差。因此，我们的数据为GPER介导的化学耐药性提供了新颖的见解，并为GPER / ABCG2信号轴成为晚期ER +他莫昔芬耐药性乳腺癌患者的化学耐药性逆转提供了有希望的靶点。他莫昔芬诱导的GPER / ABCG2信号转导轴在体外和体内对化疗（阿霉素）耐药性的发展中起着关键作用。临床数据进一步表明，接受抢救蒽环类药物化疗时，具有高GPER / ABCG2信号激活作用的他莫昔芬耐药患者的无进展生存期（PFS）较差。因此，我们的数据为GPER介导的化学耐药性提供了新颖的见解，并为GPER / ABCG2信号轴成为晚期ER +他莫昔芬耐药性乳腺癌患者的化学耐药性逆转提供了有希望的靶点。临床数据进一步表明，接受抢救蒽环类药物化疗时，具有高GPER / ABCG2信号激活作用的他莫昔芬耐药患者的无进展生存期（PFS）较差。因此，我们的数据为GPER介导的化学耐药性提供了新颖的见解，并为GPER / ABCG2信号轴成为晚期ER +他莫昔芬耐药性乳腺癌患者的化学耐药性逆转提供了有希望的靶点。临床数据进一步表明，接受抢救蒽环类药物化疗时，具有高GPER / ABCG2信号激活作用的他莫昔芬耐药患者的无进展生存期（PFS）较差。因此，我们的数据为GPER介导的化学耐药性提供了新颖的见解，并为GPER / ABCG2信号轴成为晚期ER +他莫昔芬耐药性乳腺癌患者的化学耐药性逆转提供了有希望的靶点。