GPER mediates decreased chemosensitivity via regulation of ABCG2 expression and localization in tamoxifen-resistant breast cancer cells

被引:29
作者
Yu, Tenghua [1 ]
Cheng, Hong [1 ]
Ding, Zhijuan [1 ]
Wang, Zhiliang [2 ]
Zhou, Lixia [3 ]
Zhao, Peng [4 ]
Tan, Shengxing [5 ]
Xu, Xue [6 ]
Huang, Xianming [7 ]
Liu, Manran [8 ]
Peng, Meixi [8 ]
Qiu, Yu-an [9 ]
机构
[1] Jiangxi Canc Hosp, Dept Breast Surg, Nanchang 330029, Jiangxi, Peoples R China
[2] Chongqing Med Univ, Affiliated Hosp 2, Dept Obstet & Gynecol, Chongqing 400010, Peoples R China
[3] Soochow Univ, Affiliated Hosp 1, Jiangsu Inst Hematol, Minist Hlth,Key Lab Thrombosis & Hemostasis, Suzhou 215006, Peoples R China
[4] Jiangxi Canc Hosp, Dept Head & Neck Surg, Nanchang 330029, Jiangxi, Peoples R China
[5] Nanchang Univ, Affiliated Hosp 1, Dept Gen Surg, Nanchang 330006, Jiangxi, Peoples R China
[6] Jiangxi Canc Hosp, Dept Ultrasonog, Nanchang 330029, Jiangxi, Peoples R China
[7] Jiangxi Canc Hosp, Dept Pathol, Nanchang 330029, Jiangxi, Peoples R China
[8] Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China
[9] Jiangxi Canc Hosp, Dept Crit Care Med, Nanchang 330029, Jiangxi, Peoples R China
基金
中国国家自然科学基金;
关键词
GPER; ABCG2; Chemotherapeutic resistance; Breast cancer; COUPLED ESTROGEN-RECEPTOR; FIBROBLASTS; DOXORUBICIN; PROLIFERATION; INHIBITION; PATHWAY; GPR30;
D O I
10.1016/j.mce.2020.110762
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:12
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