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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)‐β that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple‐negative breast cancer cells (TNBC) attenuates transforming growth factor‐β (TGF‐β) signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF‐β signaling by RLR ligands with respect to IFN‐β‐mediated tumor suppression are not well characterized. This study showed that transfection of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN‐β, which inhibits the growth of the surrounding cancer cells. In addition, IFN‐β‐induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3. Constitutively active Smad3 suppresses IFN‐β expression through the alleviation of IFN regulatory factor 3 binding to the canonical target genes, as suggested by ChIP sequencing analysis. Based on these findings, a new facet of the protumorigenic function of TGF‐β that suppresses IFN‐β expression is suggested when RLR‐mediated cancer treatment is used in TNBC. [ABSTRACT FROM AUTHOR]

Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2‐dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD2‐mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐SMAD2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer. A CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. [ABSTRACT FROM AUTHOR]