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Breast Cancer Research
Published in: Breast Cancer Research 6/2013

Open Access 01-12-2013 | Research article

GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer

Authors: Zhiqiang Mo, Manran Liu, Fangfang Yang, Haojun Luo, Zhenhua Li, Gang Tu, Guanglun Yang

Published in: Breast Cancer Research | Issue 6/2013

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Abstract

Introduction

Tamoxifen is widely used to treat hormone-dependent breast cancer, but its therapeutic benefit is limited by the development of drug resistance. Here, we investigated the role of estrogen G-protein coupled receptor 30 (GPR30) on Tamoxifen resistance in breast cancer.

Methods

Primary tumors (PTs) of breast cancer and corresponding metastases (MTs) were used to evaluate the expression of GPR30 and epidermal growth factor receptor (EGFR) immunohistochemically. Tamoxifen-resistant (TAM-R) subclones derived from parent MCF-7 cells were used to investigate the role of GPR30 in the development of tamoxifen resistance, using MTT assay, western blot, RT-PCR, immunofluorescence, ELISA and flow cytometry. TAM-R xenografts were established to assess anti-tumor effects of combination therapy with GPR30 antagonist G15 plus 4-hydroxytamoxifen (Tam), using tumor volume measurement and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).

Results

In 53 human breast cancer specimens, GPR30 expression in MTs increased compared to matched PTs; in MTs, the expression patterns of GPR30 and EGFR were closely related. Compared to parent MCF-7 cells, TAM-R cells had greater growth responses to 17β-estradiol (E2), GPR30 agonist G1 and Tam, and significantly higher activation of Mitogen-activated protein (MAP) kinases; but this increased activity was abolished by G15 or AG1478. In TAM-R cells, GPR30 cell-surface translocation facilitated crosstalk with EGFR, and reduced cAMP generation, attenuating inhibition of EGFR signaling. Combination therapy both promoted apoptosis in TAM-R cells and decreased drug-resistant tumor progression.

Conclusions

Long-term endocrine treatment facilitates the translocation of GPR30 to cell surfaces, which interferes with the EGFR signaling pathway; GPR30 also attenuates the inhibition of MAP kinases. These factors contribute to tamoxifen resistance development in breast cancer. Combination therapy with GPR30 inhibitors and tamoxifen may provide a new therapeutic option for drug-resistant breast cancer.
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Metadata
Title
GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer
Authors
Zhiqiang Mo
Manran Liu
Fangfang Yang
Haojun Luo
Zhenhua Li
Gang Tu
Guanglun Yang
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2013
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3581

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