GPER mediates enhanced cell viability and motility via non-genomic signaling induced by 17β-estradiol in triple-negative breast cancer cells

Yu, Tenghua; Liu, Manran; Luo, Haojun; Wu, Cheng‐Yi; Tang, Xi; Tang, Shifu; Hu, Ping; Yan, Yuzhao; Wang, Zhiliang; Tu, Gang

doi:10.1016/j.jsbmb.2014.05.003

Cited by 70 publications

(79 citation statements)

References 42 publications

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“…The seven-transmembrane G protein–coupled estrogen receptor (GPER, also known as GPR30), a member of G protein–coupled receptor (GPCR), has been reported to be activated by estrogen to modulate the progression of various hormone-responsive tumors including ER positive breast cancer [23]. Intriguingly, recent studies indicated that GPER was also greatly expressed in TNBC cell lines and patient tissues [24, 25]. Therefore it is worthy to investigate the role of GPER-signaling on AR-mediated proliferation of TNBC in absence of ER.…”

Section: Resultsmentioning

confidence: 99%

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

Shen

Yang

Zhang

et al. 2017

Cell Physiol Biochem

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Background/Aims: The targeted therapy for triple-negative breast cancer (TNBC) is still challenging due to poor understanding on its molecular etiology. The androgen receptor (AR) has recently emerged as a prognostic and treatment-predictive marker in breast cancer. However, the role of AR in TNBC remained elusive. Methods: Immunohistochemistry (IHC) was used to detect AR and G-protein coupled estrogen receptor (GPER) expression in tissue microarrays of 165 TNBC patients. Microarray analysis of mRNAs was performed to identify downstream regulators of AR. TNBC cells were cultured with dihydrotestosterone (DHT) alone or in combination with AR knockdown performed with AR shRNA. Cell viability and colony formation were assessed. Western blotting and qRT-PCR were used to examine protein and mRNA expression, respectively. The potential mechanism of AR-mediated GPER suppression was identified by Chromatin immunoprecipitation (ChIP) assay. AR and GPER expressions were also assessed in nude mouse xenografts by IHC. Results: IHC staining showed that the expression of AR was positively associated with tumor size, lymph node metastasis and high-grade tumor in TNBC patients. AR activation triggered by DHT suppressed GPER expression, to promote cell growth of TNBC. G-1, a GPER agonist, inhibited DHT-stimulated proliferation. Further experiments illustrated that AR suppressed GPER activation via binding directly to the promoter of GPER. Moreover, a negative correlation between AR and GPER was observed in MDA-MB-231 tumor cell xenografts and TNBC patient samples. Conclusions: The suppression of GPER via AR may be involved in the positive actions towards the TNBC progression, making it a promising therapeutic target for TNBC treatment.

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Section: Resultsmentioning

confidence: 99%

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

Shen

Yang

Zhang

et al. 2017

Cell Physiol Biochem

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“…HB-EGF in turn activates MAPK and PI3K/AKT pathways. Treatment with 17β-estradiol (E2), the GPER-specific agonist G-1 and tamoxifen (TAM) led to rapid activation of p-ERK1/2 which mediates enhanced cell viability and motility via non-genomic signaling in triple-negative breast cancer cells [70]. Not many studies have been published on GPER signaling in breast cancer stem cells, however one study found a positive correlation of GPER expression to CD133 (a putative stem cell marker) [71].…”

Section: Discussionmentioning

confidence: 99%

mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells

Karthik

Lövrot

et al. 2015

Cancer Letters

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“…These signaling cascades can phosphorylate nuclear ERs and their co-activators (AIB1/SRC-3) resulting in their activation as transcriptional regulators of target genes [42]. In addition, the G protein-coupled estrogen receptor (GPER) is another candidate molecule involved in the non-genomic signaling mediated by E2 [8] and also implicated in TAM resistance [8,42,43,44]. …”

Section: Estrogen Receptors (Erα and Erβ)mentioning

confidence: 99%

“…GPER, a seven transmembrane domain protein, has recently been identified as a novel estrogen receptor structurally distinct from the classic ERs (ERα and ERβ) [64,98]. This protein is expressed in approximately 50%–60% of all breast carcinomas [64,99], in endometrial and ovarian cancer cells, in thyroid carcinoma cell lines [29], in ERα-positive (MCF7), ERα-negative (SKBR3) and triple negative breast cancer (TNBC) cells [42]. …”

Section: Tam Resistancementioning

confidence: 99%

“…While it is well known that ERα-positivity is a predictor of response to TAM, it is also clear that 5%–10% of ERα-negative patients do benefit from adjuvant TAM treatment [75,76,77,114]. In these cells, TAM enhances mRNA and protein expression of CCNA1 and CCND1 after 3 h and 12 h of treatment, indicating not only that TAM regulates cell cycle progression via GPER/EGFR/ERK signaling but also suggesting a link between estrogen, TAM and GPER in TNBC (Figure 5) [42]. Taken together, these studies not only provide evidence for the important role of GPER in the development of TAM resistance in TNBC cells, but also pinpoint a potential target therapy aimed at overcoming the resistance to this endocrine treatment.…”

Section: Tam Resistancementioning

confidence: 99%

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Tamoxifen Resistance: Emerging Molecular Targets

Rondón-Lagos

Villegas

Rangel

et al. 2016

IJMS

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17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer.

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GPER mediates enhanced cell viability and motility via non-genomic signaling induced by 17β-estradiol in triple-negative breast cancer cells

Cited by 70 publications

References 42 publications

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells

Tamoxifen Resistance: Emerging Molecular Targets

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