AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer.

Yichun Qiao,Chiou-Nan Shiue,Karin Dahlman-Wright,Jian Zhu,Philip Jonsson,Ting Zhuang,Anthony P.H Wright,Chunyan Zhao

doi:10.18632/oncotarget.3158

Yichun Qiao, Chiou-Nan Shiue + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.3158

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Journal: Oncotarget	Publication Date: Jan 30, 2015
Citations: 51	License type: cc-by

Affiliation: Karolinska Institutet, University of Houston

Abstract

The molecular determinants of malignant cell behaviour in triple-negative breast cancer (TNBC) are poorly understood. Recent studies have shown that regulators of epithelial-mesenchymal transition (EMT) are potential therapeutic targets for TNBC. In this study, we demonstrate that the inflammatory cytokine TNFα induces EMT in TNBC cells via activation of AP-1 signaling and subsequently induces expression of the EMT regulator ZEB2. We also show that TNFα activates both the PI3K/Akt and MAPK/ERK pathways, which act upstream of AP-1. We further investigated in detail AP-1 regulation of ZEB2 expression. We show that two ZEB2 transcripts derived from distinct promoters are both expressed in breast cancer cell lines and breast tumor samples. Using the chromosome conformation capture assay, we demonstrate that AP-1, when activated by TNFα, binds to a site in promoter 1b of the ZEB2 gene where it regulates the expression of both promoter 1b and 1a, the latter via mediating long range chromatin interactions. Overall, this work provides a plausible mechanism for inflammation-induced metastatic potential in TNBC, involving a novel regulatory mechanism governing ZEB2 isoform expression.

Highlights

Triple-negative breast cancer (TNBC), a tumor type defined by lack of expression of the estrogen, progesterone and HER2 receptors, represents a more aggressive and metastatic form of breast cancer than other types of breast cancer [1]
We show that TNFα activates both the PI3K/Akt and MAPK/ERK pathways, which act upstream of AP-1
In the following set of experiments, we explored whether the AP-1–ZEB2 axis mediates TNFα-induced epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells

Summary

Introduction

Triple-negative breast cancer (TNBC), a tumor type defined by lack of expression of the estrogen, progesterone and HER2 receptors, represents a more aggressive and metastatic form of breast cancer than other types of breast cancer [1]. Treatment of patients with TNBC is challenging. Whilst breast tumors that express estrogen receptor (ER) are responsive to ER antagonists and aromatase inhibitors and HER2-positive tumors are effectively treated with HER2-blocking antibodies and/or HER2 kinase inhibitors [2], TNBC lacks a targeted therapy. Understanding the molecular pathways determinant for TNBC behaviour is one strategy for developing more effective treatments for TNBCs. The transcription factor AP-1 consists of different dimeric combinations of either homodimers of Jun proteins (c-Jun, JunB and JunD) or heterodimers of Jun and Fos proteins (c-Fos, FosB, Fra-1 and Fra-2). Upon activation by growth factors, hormones or cytokines, AP-1 signaling plays a critical role in numerous cellular processes, including proliferation, differentiation, apoptosis, cell migration, and transformation [4]

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