Activation of GPER suppresses epithelial mesenchymal transition of triple negative breast cancer cells via NF‐κB signals

Chen, Zhuo Jia; Wei, Wei; Jiang, Guan; Líu, Hao; Wei, Wei Dong; Yang, Xiangling; Wu, Ying; Liu, Huanliang; Wong, Chris K C; Du, Jie; Wang, Hong Sheng

doi:10.1016/j.molonc.2016.01.002

Cited by 67 publications

(78 citation statements)

References 57 publications

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“…Further in vitro researches illustrated that activation of GPER through G-1 attenuated DHT–induced proliferation. Coincidentally, our current data are consistent with another study indicating that G-1 inhibited the in vivo growth and invasive potential of TNBC [43]. Consistent to the in vitro studies, the negative correlation of AR and GPER was confirmed in patient tissues and nude mouse xenografts.…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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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“…Others linked GPER with a better OS and DFS, and in a further study on invasive breast cancer, GPER expression was more common in smaller tumours . In triple‐negative breast cancer, GPER expression was positively correlated with a favourable patient outcome, and negatively with high tumour grade and lymph node metastasis, an effect most likely mediated by inhibition of epithelial mesenchymal transition . Based on novel observations new, GPER‐targeted therapies are in pipeline to better target triple‐negative breast cancer .…”

Section: Discussionmentioning

confidence: 96%

“…[58][59][60] In triple-negative breast cancer, GPER expression was positively correlated with a favourable patient outcome, and negatively with high tumour grade and lymph node metastasis, an effect most likely mediated by inhibition of epithelial mesenchymal transition. 61 Based on novel observations new, GPER-targeted therapies are in pipeline to better target triple-negative breast cancer. [62][63][64] In seminomas and in situ testicular carcinomas, the down regulation of ERb expression together with GPER overexpression conferred oestrogen responsiveness.…”

Section: Discussionmentioning

confidence: 99%

Expression of G protein‐coupled oestrogen receptor in melanoma and in pregnancy‐associated melanoma

Fábián

Rencz

Krenács

et al. 2017

Acad Dermatol Venereol

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“…Although we did not perform a detailed analysis to clarify the cell proliferation effect of GPER on macrophages, GPER has been suggested to negatively regulate inflammatory cytokine expression pathways (and not affect cell proliferation). Furthermore, GPER suppresses epithelial mesenchymal transition, migration and angiogenesis of triple negative breast cancer cells via inhibition of the NF-jB signal (Chen et al 2016;Liang et al 2017). S2).…”

Section: Discussionmentioning

confidence: 99%

The membrane‐type estrogen receptor G‐protein‐coupled estrogen receptor suppresses lipopolysaccharide‐induced interleukin 6 via inhibition of nuclear factor‐kappa B pathway in murine macrophage cells

Okamoto

Suzuki

Mizukami

et al. 2017

Animal Science Journal

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The female sex hormone estrogen exerts anti-inflammatory effects. The G-protein-coupled estrogen receptor (GPER) has been recently identified as a novel membrane-type estrogen receptor that can mediate non-genomic estrogenic effects on many cell types. We previously demonstrated that GPER inhibits tumor necrosis factor alpha-induced expression of interleukin 6 (IL-6) through repression of nuclear factor-kappa B (NF-κB) promoter activity using human breast cancer cells. Although several reports have indicated that GPER suppresses Toll-like receptor-induced inflammatory cytokine expression in macrophages, the molecular mechanisms of the inhibition of cytokine production via GPER remain poorly understood. In the present study, we examined GPER-mediated inhibition of IL-6 expression induced by lipopolysaccharide (LPS) stimulation in a mouse macrophage cell line. We found that the GPER agonist G-1 inhibited LPS-induced IL-6 expression in macrophage cells, and this inhibition was due to the repression of NF-κB promoter activity by GPER. G-1 treatment also decreased the phosphorylation of inhibitor of κB kinases. Among the mitogen-activated protein kinases, the phosphorylation of c-jun N-terminal kinase (JNK) was increased by G-1. These findings delineate the novel mechanism of the inhibition of LPS-induced IL-6 through GPER-activated JNK-mediated negative regulation of the NF-κB pathway in murine macrophage cells, which links anti-inflammatory effects to estrogen.

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Activation of GPER suppresses epithelial mesenchymal transition of triple negative breast cancer cells via NF‐κB signals

Cited by 67 publications

References 57 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

Expression of G protein‐coupled oestrogen receptor in melanoma and in pregnancy‐associated melanoma

The membrane‐type estrogen receptor G‐protein‐coupled estrogen receptor suppresses lipopolysaccharide‐induced interleukin 6 via inhibition of nuclear factor‐kappa B pathway in murine macrophage cells

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