IRF3 drives replication stress signaling and determines sensitivity to genotoxic agents in triple-negative breast cancer cells

Interferon-β signaling has been shown to play important roles in anti-virus as well as anti-tumor immunity. We here report that the key transcription factor in type I interferon signaling, IRF3, as well as downstream interferon-β are able to induce replication stress signaling in triple-negative breast cancer cells. IRF3 overexpression sensitizes triple-negative breast cancer cells to several genotoxic agents. Addition of IFN-β, a key downstream cytokine of IRF3,reduced replication fork speed and activated ATR-CHK1 signaling. Conversely, type I interferon-neutralizing antibodies or nucleosides supplementation rescued IRF3-induced replication stress. We treated two triple-negative breast cancer cell lines, HCC38 and MDA-MB-231, with interferon-β (400 IU/mL) for 48 hours. We then performed gene expression profiling analysis using data obtained from RNA-seq of untreated samples and interferon-β-treated samples.