Chronic Interferon-stimulated Gene Transcription Promotes Oncogene-induced Breast Cancer

The MRE11 complex (comprising MRE11, RAD50, and NBS1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic mutant mouse strain ( ) was highly susceptible to oncogene-induced breast cancer. Here we used a mammary organoid system to examine which MRE11-dependent responses are tumor-suppressive. We found that organoids exhibited an elevated interferon-stimulated gene (ISG) signature and sustained changes in chromatin accessibility. This phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation of in organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed in WT. Implantation of organoids and activation of the oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implanted organoids. These data reveal a connection between innate immune signaling and tumor development in the mammary epithelium. Given the abundance of aberrant DNA structures that arise in the context of genome instability syndromes, the data further suggest that cancer predisposition in those contexts may be partially attributable to chronic innate immune transcriptional programs.