Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers

Significance In a breast cellular transformation model, we describe the gene regulatory network that is mediated by joint and direct action of three inflammatory transcription factors on hundreds of target genes in various oncogenic pathways. This inflammatory feedback loop and associated network functions in many types of cancer cells and patient tumors. It forms the basis for a “cancer inflammation index” that defines cancer types by functional criteria, and that may be useful for choosing drugs for personalized cancer treatment. Inflammatory tumor cells, via secreted inflammatory molecules, might help recruit immune cells to the site of the tumor. Thus, detailed analysis of an artificial transformation model uncovers the molecular basis of an inflammatory network relevant for many forms of human cancer. Using an inducible, inflammatory model of breast cellular transformation, we describe the transcriptional regulatory network mediated by STAT3, NF-κB, and AP-1 factors on a genomic scale. These proinflammatory regulators form transcriptional complexes that directly regulate the expression of hundreds of genes in oncogenic pathways via a positive feedback loop. This transcriptional feedback loop and associated network functions to various extents in many types of cancer cells and patient tumors, and it is the basis for a cancer inflammation index that defines cancer types by functional criteria. We identify a network of noninflammatory genes whose expression is well correlated with the cancer inflammatory index. Conversely, the cancer inflammation index is negatively correlated with the expression of genes involved in DNA metabolism, and transformation is associated with genome instability. We identify drugs whose efficacy in cell lines is correlated with the cancer inflammation index, suggesting the possibility of using this index for personalized cancer therapy. Inflammatory tumors are preferentially associated with infiltrating immune cells that might be recruited to the site of the tumor via inflammatory molecules produced by the cancer cells.

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