BioProject

Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. More...

Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFalpha can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically, we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-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. Overall design: BT549 cells were cultured to 50% confluency and transfected with control or c-Jun siRNA for 72 hours, followed by treatment with or without TNFα for 6 hours. Less...