title: AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression.
abstract: Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFα can facilitate tumor progression and metastasis. However, the mechanistic aspects of inflammation mediated TNBC progression remain unclear. Using ChIP-seq, we demonstrate that the cistrome for the AP-1 transcription factor c-Jun is comprised of 13,800 binding regions in TNFα-stimulated TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFα-regulated transcriptome. Interestingly, high expression level of the c-Jun-regulated pro-invasion gene program is associated with poor clinical outcome in TNBCs. We further demonstrate that c-Jun drives TNFα-mediated increase of malignant characteristics of TNBC cells by transcriptional regulation of Ninj1. As exemplified by the CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-κB might be a pioneer factor required for the regulation of TNFα-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response.
authors.affiliation: From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden.
authors.forename: Huan
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, and.
authors.forename: Philip
authors.initials: P
authors.lastname: Jonsson
authors.affiliation: From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden.
authors.forename: Indranil
authors.initials: I
authors.lastname: Sinha
authors.affiliation: From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden, chunyan.zhao@ki.se.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
authors.affiliation: From the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, S-141 83 Huddinge, Sweden, Science for Life Laboratory, Karolinska Institutet, S-171 21 Solna, Sweden karin.dahlman-wright@ki.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Dahlman-Wright
mesh_terms: D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016328:NF-kappa B; C484438:NINJ1 protein, human; D009414:Nerve Growth Factors; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha
keywords: AP1 transcription factor (AP-1); ChIP-sequencing (ChIP-seq); breast cancer; gene expression; tumor necrosis factor (TNF)