| 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. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: |
controlled study; unclassified drug; oncoprotein; major clinical study; genetics; metabolism; apoptosis; genes; gene expression; immunoglobulin enhancer binding protein; nerve growth factors; pathology; cell line, tumor; gene expression regulation; oncogene; gene expression regulation, neoplastic; transcription regulation; tumor necrosis factor alpha; tumor necrosis factor-alpha; chromatin immunoprecipitation; nf-kappa b; tumor cell line; nerve cell adhesion molecule; transcription; binding site; transcriptome; cell invasion; diseases; transcriptional regulation; tumor necrosis factor; triple negative breast cancer; transcription factor ap 1; inflammatory genes; chromosome 4; chromosomes, human, pair 4; alpha chemokine; cancer progression; inflammatory response; nerve growth factor; protein c jun; transcription factor ap-1; tumor progressions; cancer prognosis; proto-oncogene proteins c-jun; pro-inflammatory cytokines; humans; human; female; priority journal; article; cell adhesion molecules, neuronal; breast cancer cell line; mechanistic aspects; triple-negative breast cancers; c (programming language); nerve injury induced protein 1; ninj1 gene; ninj1 protein, human; triple negative breast neoplasms
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