ARF and p53 Coordinate Tumor Suppression of an Oncogenic IFN-β-STAT1-ISG15 Signaling Axis

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. [Display omitted] •Endogenous ARF inhibits the proliferation and tumorigenicity of p53-deficient cells•ARF and p53 cooperate to suppress an oncogenic type I interferon response•p53 mutant breast tumors with low ARF levels contain high STAT1 and ISG15•p53 mutant breast cancer cells lacking ARF are sensitive to STAT1 inhibition 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.