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

Abstract

The targeted therapy for triple-negative breast cancer (TNBC) is a great challenge due to our poor understanding on its molecular etiology. In the present study, our clinical data showed that the expression of G-protein coupled estrogen receptor (GPER) is negatively associated with lymph node metastasis, high-grade tumor and fibronectin (FN) expression while positively associated with the favorable outcome in 135 TNBC patients. In our experimental studies, both the in vitro migration and invasion of TNBC cells were inhibited by GPER specific agonist G-1, through the suppression of the epithelial mesenchymal transition (EMT). The G-1 treatment also reduced the phosphorylation, nuclear localization, and transcriptional activities of NF-κB. While over expression of NF-κB attenuated the action of G-1 in suppressing EMT. Our data further illustrated that the phosphorylation of GSK-3β by PI3K/Akt and ERK1/2 mediated, at least partially, the inhibitory effect of G-1 on NF-κB activities. It was further confirmed in a study of MDA-MB-231 tumor xenografts in nude mice. The data showed that G-1 inhibited the in vivo growth and invasive potential of TNBC via suppression of EMT. Our present study demonstrated that an activation of GPER pathway elicits tumor suppressive actions on TNBC, and supports the use of G-1 therapeutics for TNBC metastasis.

• Authors: Zhuo-Jia Chen, Wei Wei, Guan-Min Jiang, Hao Liu, Wei-Dong Wei, Xiangling Yang, Ying-Min Wu, Huanliang Liu, Chris K C Wong, Jun Du, Hong-Sheng Wang
• Journal: Molecular oncology (Mol Oncol) Vol. 10 Issue 6 Pg. 775-88 (06 2016) ISSN: 1878-0261 [Electronic] United States
• PMID: 26842883 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Fibronectins
• GPER1 protein, human
• NF-kappa B
• Receptors, Estrogen
• Receptors, G-Protein-Coupled
• Phosphatidylinositol 3-Kinases
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Breast (metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Epithelial-Mesenchymal Transition
• Female
• Fibronectins (analysis, metabolism)
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• MAP Kinase Signaling System
• Mice, Nude
• Middle Aged
• NF-kappa B (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Estrogen (analysis, genetics, metabolism)
• Receptors, G-Protein-Coupled (analysis, genetics, metabolism)
• Signal Transduction
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)