PolyI:C attenuates transforming growth factor-β signaling to induce cytostasis of surrounding cells by secreted factors in triple-negative breast cancer

Cancer Sci. 2022 Mar;113(3):940-949. doi: 10.1111/cas.15241. Epub 2021 Dec 23.


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.

Keywords: IFN-β; IRF3; TGF-β; TNBC; polyI:C.

MeSH terms

  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-beta / metabolism*
  • Poly I-C / genetics
  • Poly I-C / pharmacology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transfection
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / metabolism
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Microenvironment / drug effects


  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Interferon-beta
  • Poly I-C