HER2 overexpression triggers an IL-1{alpha} pro-inflammatory circuit to drive tumorigenesis and promote chemotherapy resistance

Systemic inflammation in breast cancer correlates with poor prognosis but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation and expansion of the mammary stem/progenitor and cancer stem-like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feed-forward activation loop of IL-1α and IL-6 that stimulated NF-κB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2-induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL-1α/IL-6 expression and CSC-positive phenotype. Pharmacologic blockade of IL-1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2E2sGEM