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Oncotarget. 2015 Apr 10;6(10):7804-14.

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

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Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
Clinical Research Center (KFC), Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
Department of Pediatrics, Hualien Tzu Chi Hospital, Buddist Tzu Chi Medical Foundation, Hualien, Taiwan.
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, USA.
Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.


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.


AP-1; TNFα; ZEB2; epithelial–mesenchymal transition; triple-negative breast cancer

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