AP-1 Is a Key Regulator of Proinflammatory Cytokine TNF?-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 TNF? 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 TNF?-stimulated TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNF?-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 TNF?-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-?B might be a pioneer factor required for the regulation of TNF?-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.

SUBMITTER: Qiao Y 

PROVIDER: S-EPMC4777842 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature