Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

Abstract

AbstractThe Mre11 complex (comprising Mre11, Rad50, Nbs1) is integral to the maintenance of genome stability. We previously showed that a hypomorphicMre11mutant mouse strain (Mre11ATLD1/ATLD1) 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 thatMre11ATLD1/ATLD1organoids exhibited an elevated interferon stimulated gene (ISG) signature and sustained changes in chromatin accessibility. ThisMre11ATLD1/ATLD1phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation ofIfi205inMre11ATLD1/ATLD1organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed inWT. Implantation ofMre11ATLD1/ATLD1organoids and activation of oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implantedIfi205-/-Mre11ATLD1/ATLD1organoids. These data reveal a connection between innate immune signaling and tumor suppression in 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 tonic innate immune transcriptional programs.