BRCA1 deficiency induces NFκB-dependent type-I interferon signaling in fallopian tube epithelial cells.

BRCA1 mutation confers elevated risk for high-grade serous tubal-ovarian cancer (HGSTOC) arising from the fallopian tube epithelium (FTE) and is associated with increased proinflammatory NFκB signaling. Recent evidence indicates this signaling may be mediated by stimulation of cGAS-STING, a pattern recognition receptor (PRR), that can also activate IRF3 to drive type-I interferon (IFN-I) production and increased expression of interferon-stimulated genes. We investigated the impact of CRISPR-Cas9 generated homozygous and heterozygous disruption of BRCA1 on IFN-I signaling in FTE cells. Loss of BRCA1 associated with increased activation of IRF3, STAT2, and increased levels of IFN-I target gene transcripts and protein, including ISG15, USP18 and ISGylation. In contrast, a consistent increase in canonical or non-canonical NFκB activation or downstream target gene expression was not observed. Inhibition of TBK1, which mediates activation of IRF3 by multiple PRRs, blocked the increase in both ISG15 and USP18 whereas the increase in USP18 but not ISG15 in BRCA1-disrupted cells was partially blocked by inhibition of STING. Inhibition of NFκB activation or IFN-I signaling decreased elevated levels of IFN-I-stimulated genes with no further inhibition provided by combining inhibitors. These findings indicate that BRCA1 deficiency preferentially enhances proinflammatory IFN-I signaling in an NFκB-permissive manner and support further investigation of targeting PRR signaling in FTE cells as a potential strategy to mitigate the risk of HGSTOC in BRCA1 mutation carriers.