IRF3 and Smad3 binding regions in a basal-like breast cancer cell line, BT549 transfected with polyI:C.

The activation of RIG-I-like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand-mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)-ß that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple-negative breast cancer cells (TNBC) attenuates TGF-ß signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF-ß signaling by RLR ligands with respect to IFN-ß-mediated tumor suppression are not well characterized. This study showed that cytosolic induction of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN-ß, which inhibits the growth of the surrounding cancer cells. In addition, IFN-ß-induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3 (caSmad3). caSmad3 suppresses IFN-ß expression through the alleviation of IRF3 binding to the canonical target genes, as suggested by ChIP-seq analysis. Based on these findings, a new facet of the pro-tumorigenic function of TGF-ß that suppresses IFN-ß expression is suggested when exploiting RLR-mediated cancer treatment in TNBC. Overall design: IRF3 and Smad3 ChIP-seq analysis was performed in a basal-like breast cancer cell line, BT549 cells transfected with polyI:C. Constitutively active Smad3 was stably expressed to rescue the inhibitory effect of polyI:C.