GPER1 promotes estrogen receptor negative breast cancer cell migration and invasion via non-genomic activation of c-Src/NF-&kgr;B/focal adhesion kinase cascade

Xiaosa Li, Qing Yan, Xingyan Xu, Weiyu Chen, Ping Li, Qiumei Xiang, Xiaoyang Xu, Xiaodong Fu
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引用次数: 1

Abstract

Abstract Breast cancer metastasis is the root cause of deaths from breast cancer. Currently, endocrine therapy resistance in estrogen receptor (ER)-positive (ER+) breast cancer remains a major clinical issue. Moreover, ER-negative (ER−) breast cancer is often associated with distant recurrence and death. G-protein-coupled ER (GPER1) participates in endocrine therapy resistance and is involved in the malignant progression of breast cancer. However, the underlying detailed mechanisms remain obscure. Here we investigated the role and mechanism of GPER1 in the activation of focal adhesion kinase (FAK) using ER+ or ER− breast cancer cell lines. In SK-Br-3 cells (ER&agr;−/&bgr;−/GPER1+), both 17&bgr;-estradiol (E2) and the GPER1 agonist G1 resulted in rapid FAK phosphorylation. This action is due to GPER1 interaction with the non-receptor tyrosine kinase c-Src and subsequent activation of nuclear factor kappa B (NF-&kgr;B) signaling. Silencing of GPER1, c-Src or the nuclear factor kappa B p65 subunit blocked E2- or G1-induced SK-Br-3 cell migration and invasion. In MCF-7 cells (ER&agr;+/&bgr;+/GPER1+), silencing of GPER1, but not ER&agr; or ER&bgr;, abolished FAK phosphorylation induced by E2 or G1. In MDA-MB-231 cells (ER&agr;−/&bgr;+/GPER1−), E2 or G1 was also unable to stimulate E2-induced FAK phosphorylation. However, E2 and G1 regained the ability to induce FAK phosphorylation under conditions of overexpression of GPER1. In conclusion, we demonstrated that GPER1, but not ER&agr; or ER&bgr;, mediates FAK phosphorylation induced by E2 via the c-Src/p65 signaling pathway, which enhances cell migration and invasion. These findings may shed light on novel therapeutic strategies based on GPER1/FAK signaling pathways in suppression of breast cancer metastasis.
GPER1通过非基因组激活c-Src/NF-&kgr;B/局灶黏附激酶级联促进雌激素受体阴性乳腺癌细胞的迁移和侵袭
乳腺癌转移是乳腺癌死亡的根本原因。目前,雌激素受体(ER)阳性(ER+)乳腺癌的内分泌治疗抵抗仍然是一个主要的临床问题。此外,ER阴性(ER−)乳腺癌通常与远处复发和死亡有关。g蛋白偶联内质网(GPER1)参与内分泌治疗抵抗,参与乳腺癌的恶性进展。然而,潜在的详细机制仍然不清楚。本研究利用ER+或ER -乳腺癌细胞系研究了GPER1在局灶黏附激酶(FAK)活化中的作用和机制。在SK-Br-3细胞(ER&agr;−/&bgr;−/GPER1+)中,17&bgr;-雌二醇(E2)和GPER1激动剂G1均导致FAK快速磷酸化。这种作用是由于GPER1与非受体酪氨酸激酶c-Src相互作用以及随后激活核因子κ B (NF-&kgr;B)信号传导。沉默GPER1、c-Src或核因子κ B p65亚基可阻断E2-或g1诱导的SK-Br-3细胞迁移和侵袭。在MCF-7细胞(ER&agr +/&bgr +/GPER1+)中,GPER1沉默,而ER&agr不沉默;或ER&bgr;,消除E2或G1诱导的FAK磷酸化。在MDA-MB-231细胞(ER&agr;−/&bgr;+/GPER1−)中,E2或G1也不能刺激E2诱导的FAK磷酸化。然而,在GPER1过表达的条件下,E2和G1恢复了诱导FAK磷酸化的能力。总之,我们证明了GPER1,而不是ER&agr;或ER&bgr;通过c-Src/p65信号通路介导E2诱导的FAK磷酸化,从而增强细胞迁移和侵袭。这些发现可能揭示了基于GPER1/FAK信号通路抑制乳腺癌转移的新治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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