ARF and p53 Coordinate Tumor Suppression of an Oncogenic IFN-β-STAT1-ISG15 Signaling Axis
Jason T. Forys,
Catherine E. Kuzmicki,
Anthony J. Saporita,
Crystal L. Winkeler,
Leonard B. Maggi, Jr.,
Jason D. Weber
Affiliations
Jason T. Forys
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA
Catherine E. Kuzmicki
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA
Anthony J. Saporita
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA
Crystal L. Winkeler
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA
Leonard B. Maggi, Jr.
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA
Jason D. Weber
BRIGHT Institute, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Division of Molecular Oncology, Department of Internal Medicine, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Cell Biology and Physiology, Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA; Corresponding author
Summary: The ARF and p53 tumor suppressors are thought to act in a linear pathway to prevent cellular transformation in response to various oncogenic signals. Here, we show that loss of p53 leads to an increase in ARF protein levels, which function to limit the proliferation and tumorigenicity of p53-deficient cells by inhibiting an IFN-β-STAT1-ISG15 signaling axis. Human triple-negative breast cancer (TNBC) tumor samples with coinactivation of p53 and ARF exhibit high expression of both STAT1 and ISG15, and TNBC cell lines are sensitive to STAT1 depletion. We propose that loss of p53 function and subsequent ARF induction creates a selective pressure to inactivate ARF and propose that tumors harboring coinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation. : A detailed understanding of cancer cell vulnerabilities based on specific genetic and molecular signatures is imperative. In pursuit of this endeavor, Forys et al. have uncovered a proproliferative pathway that drives tumorigenesis in cells lacking the p53 and ARF tumor suppressors. They identified this oncogenic pathway as a type I interferon response mediated by IFN-β, STAT1, and ISG15. The authors further demonstrate the potential therapeutic efficacy of targeting this pathway in a subset of breast cancer patients.
