Research Papers:

NHERF1, a novel GPER associated protein, increases stability and activation of GPER in ER-positive breast cancer

Ran Meng, Qiong Qin, Ying Xiong, Yan Wang, Junfang Zheng, Yuan Zhao, Tao Tao, Qiqi Wang, Hua Liu, Songlin Wang, Wen G. Jiang and Junqi He _

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Oncotarget. 2016; 7:54983-54997. https://doi.org/10.18632/oncotarget.10713

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Ran Meng1,*, Qiong Qin1,2,*, Ying Xiong1,2, Yan Wang1, Junfang Zheng1,2, Yuan Zhao1, Tao Tao1, Qiqi Wang1, Hua Liu1,2, Songlin Wang1,3, Wen G. Jiang2,4, Junqi He1,2

1Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, China

2Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing International Cooperation Base for Science and Technology on China-UK Cancer Research, Beijing, China

3Molecular Laboratory for Gene Therapy and Tooth Regeneration, Capital Medical University School of Stomatology, Beijing, China

4Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, United Kingdom

*These authors contributed equally to this work

Correspondence to:

Junqi He, email: [email protected]

Keywords: G protein-coupled receptor, EBP50, protein-protein interaction, protein degradation, carcinogenesis

Received: January 15, 2016     Accepted: June 12, 2016     Published: July 19, 2016


G protein-coupled estrogen receptor (GPER) plays an important role in mediating the effects of estradiol. High levels of GPER have been implicated to associate with the malignant progress of invasive breast cancer (IBC). However, the mechanisms by which GPER protein levels were regulated remain unclear. In this study, PDZ protein Na+/H+ exchanger regulatory factor (NHERF1) was found to interact with GPER in breast cancer cells. This interaction was mediated by the PDZ2 domain of NHERF1 and the carboxyl terminal PDZ binding motif of GPER. NHERF1 was demonstrated to facilitate GPER expression at post-transcriptional level and improve GPER protein stability by inhibiting the receptor degradation via ubiquitin-proteasome pathway in a GPER/NHERF1 interaction-dependent manner. In addition, GPER protein levels are positively associated with NHERF1 protein levels in a panel of estrogen receptor (ER)-positive breast cancer cells. Furthermore, analysis of clinical IBC data from The Cancer Genome Atlas (TCGA) showed no significant difference in GPER mRNA levels between ER-positive IBC and normal breast tissues. However, gene set enrichment analysis (GSEA) showed that GPER signaling is ultra-activated in ER-positive IBC when compared with normal and its activation is positively associated with NHERF1 mRNA levels. Taken together, our findings identify NHERF1 as a new binding partner for GPER and its overexpression promotes protein stability and activation of GPER in ER-positive IBC. Our data indicate that regulation of GPER stability by NHERF1 may contribute to GPER-mediated carcinogenesis in ER-positive IBC.

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