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

Yu, Tenghua; Cheng, Hong; Ding, Zhijuan; Wang, Zhiliang; Zhang, Lixia; Zhao, Pengchao; Tan, Shengxing; Xue, Xu; Huang, Xianming; Liu, Manran; Peng, Meixi; Qiu, Yuan

doi:10.1016/j.mce.2020.110762

Cited by 29 publications

(36 citation statements)

References 44 publications

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“…Thus, coupling of IL1β secretion by cancer-associated fibroblasts to the expression of IL-1R1 by cancer cells, promotes a positive regulation of protumoral genes such as those for COX-2 and ATP-binding cassette super-family G member 2 ( 46 ). Yu et al., 2020 ( 47 ) reported that ERα positive metastatic tissue shows increased levels of GPER-1 and ATP-binding cassette super-family G member 2 genes, which have been involved with multiresistance to different types of chemotherapy. Additionally, treatment of tamoxifen-resistant MCF-7 cells with G1 or with Fulvestrant (ICI 182,780) significantly increased GPER-1 expression, when compared to non-resistant MCF-7 cells ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…Yu et al., 2020 ( 47 ) reported that ERα positive metastatic tissue shows increased levels of GPER-1 and ATP-binding cassette super-family G member 2 genes, which have been involved with multiresistance to different types of chemotherapy. Additionally, treatment of tamoxifen-resistant MCF-7 cells with G1 or with Fulvestrant (ICI 182,780) significantly increased GPER-1 expression, when compared to non-resistant MCF-7 cells ( 47 ). Pharmacological therapies can also alter intracellular signaling cascades such as [Ca 2+ ] i signaling, a key pathway in which calcium itself acts as second messenger or may participate in signal transduction to open ion channels.…”

Section: Discussionmentioning

confidence: 99%

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Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation

et al. 2020

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GPER-1 is a novel membrane sited G protein-coupled estrogen receptor. Clinical studies have shown that patients suffering an estrogen receptor a (ERa)/GPER-1 positive, breast cancer have a lower survival rate than those who have developed ERa-positive/GPER-1 negative tumors. Moreover, absence of GPER-1 improves the prognosis of patients treated with tamoxifen, the most used selective estrogen receptor modulator to treat ERapositive breast cancer. MCF-7 breast cancer cells were continuously treated with 1,000 nM tamoxifen for 7 days to investigate its effect on GPER-1 protein expression, cell proliferation and intracellular [Ca 2+ ]i mobilization, a key signaling pathway. Breast cancer cells continuously treated with tamoxifen, exhibited a robust [Ca 2+ ]i mobilization after stimulation with 1,000 nM tamoxifen, a response that was blunted by preincubation of cells with G15, a commercial GPER-1 antagonist. Continuously treated cells also displayed a high [Ca 2+ ]i mobilization in response to a commercial GPER-1 agonist (G1) and to estrogen, in a magnitude that doubled the response observed in untreated cells and was almost completely abolished by G15. Proliferation of cells continuously treated with tamoxifen and stimulated with 2,000 nM tamoxifen, was also higher than that observed in untreated cells in a degree that was approximately 90% attributable to GPER-1. Finally, prolonged tamoxifen treatment did not increase ERa expression, but did overexpress the kinin B1 receptor, another GPCR, which we have previously shown is highly expressed in breast tumors and increases proliferation of breast cancer cells. Although we cannot fully extrapolate the results obtained in vitro to the patients, our results shed some light on the occurrence of drug resistance in breast cancer patients who are ERa/GPER-1 positive, have been treated with tamoxifen and display low survival rate. Overexpression of kinin B1 receptor may explain the increased proliferative response observed in breast tumors under continuous treatment with tamoxifen.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation

et al. 2020

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“…The biological functions of GPER are inconsistent between different cells and organs. Our previous studies indicated that the activation of GPER enhances the viability of and confers multidrug resistance to breast cancer cells (22)(23)(24). Conversely, GPER activation inhibits cell proliferation and increases apoptosis in gastric and colorectal cancers (25,26).…”

Section: Introductionmentioning

confidence: 99%

GPER-Induced ERK Signaling Decreases Cell Viability of Hepatocellular Carcinoma

Qiu

Xiong

et al. 2021

Front. Oncol.

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Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis. Effective biomarkers and specific therapeutic targets for HCC are therefore urgently needed. G protein-coupled estrogen receptor (GPER) plays a crucial role in numerous cancer types; however, its functions in HCC require further exploration. In the present study, we found a remarkable difference in GPER staining between tumor tissue (100/141, 70.9%) and matched non-tumor tissue (27/30, 90.0%). Compared with the GPER-negative patients, the GPER-positive patients with HCC were closely associated with female sex, negative hepatitis B surface antigen, small tumor size, low serum alpha fetoprotein level, and longer overall survival. Treatment with GPER-specific agonist G1 led to the sustained and transient activation of the EGFR/ERK and EGFR/AKT signaling pathways, respectively, in the HCC cell lines HCCLM3 and SMMC-7721, which express high levels of GPER. Interestingly, G1-induced EGFR/ERK signaling, rather than EGFR/AKT signaling mediated by GPER, was involved in decreasing cell viability by blocking cell cycle progression, thereby promoting apoptosis and inhibiting cell growth. Clinical analysis indicated that simultaneous high expression of GPER and phosphorylated-ERK (p-ERK) predicted improved prognosis for HCC. Finally, the activation of GPER/ERK signaling remarkably suppressed tumor growth in an HCC xenograft model, and this result was consistent with the in vitro data. Our findings suggest that specific activation of the GPER/ERK axis may serve as a novel tumor-suppressive mechanism and that this axis could be a therapeutic target for HCC.

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“…Reversal of ABCG2-mediated MDR may result from various reasons including modification of ABCG2 mRNA transcription or protein expression (Liao et al, 2019), alteration of intracellular localization of ABCG2 (Yu et al, 2020), modulation of signaling pathways (Zhang et al, 2020a), interaction with ABCG2associated ATPase (Wang et al, 2020a) and direct interaction with the drug binding sites of ABCG2 (Cai et al, 2020;Wang et al, 2020a). In this study, we tested the effect of AZ-628 on the protein expression level as well as intracellular localization of ABCG2.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

Wang

Teng

Lei

et al. 2020

Front. Cell Dev. Biol.

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Overexpression of ABCG2 remains a major impediment to successful cancer treatment, because ABCG2 functions as an efflux pump of chemotherapeutic agents and causes clinical multidrug resistance (MDR). Therefore, it is important to uncover effective modulators to circumvent ABCG2-mediated MDR in cancers. In this study, we reported that AZ-628, a RAF kinase inhibitor, effectively antagonizes ABCG2-mediated MDR in vitro. Our results showed that AZ-628 completely reversed ABCG2-mediated MDR at a non-toxic concentration (3 μM) without affecting ABCB1-, ABCC1-, or ABCC10 mediated MDR. Further studies revealed that the reversal mechanism was by attenuating ABCG2-mediated efflux and increasing intracellular accumulation of ABCG2 substrate drugs. Moreover, AZ-628 stimulated ABCG2-associated ATPase activity in a concentration-dependent manner. Docking and molecular dynamics simulation analysis showed that AZ-628 binds to the same site as ABCG2 substrate drugs with higher score. Taken together, our studies indicate that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers.

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

Cited by 29 publications

References 44 publications

Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation

Continuous Exposure of Breast Cancer Cells to Tamoxifen Upregulates GPER-1 and Increases Cell Proliferation

GPER-Induced ERK Signaling Decreases Cell Viability of Hepatocellular Carcinoma

Reversal of Cancer Multidrug Resistance (MDR) Mediated by ATP-Binding Cassette Transporter G2 (ABCG2) by AZ-628, a RAF Kinase Inhibitor

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