Chronic interferon-stimulated gene transcription promotes oncogene-induced breast cancer Journal Article
| Authors: | Wang, H.; Canasto-Chibuque, C.; Kim, J. H.; Hohl, M.; Leslie, C.; Reis-Filho, J. S.; Petrini, J. H. J. |
| Article Title: | Chronic interferon-stimulated gene transcription promotes oncogene-induced breast cancer |
| Abstract: | The MRE11 complex (comprising MRE11, RAD50, and NBS1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic Mre11 mutant 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 that Mre11ATLD1/ATLD1 organoids exhibited an elevated interferon-stimulated gene (ISG) signature and sustained changes in chromatin accessibility. This Mre11ATLD1/ATLD1 phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation of Ifi205 in Mre11ATLD1/ATLD1 organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed in WT. Implantation of Mre11ATLD1/ATLD1 organoids and activation of the oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implanted Ifi205−/− Mre11ATLD1/ATLD1 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. © 2024 Wang et al. |
| Keywords: | controlled study; unclassified drug; dna binding protein; genetics; dna-binding proteins; interferon; nonhuman; mouse; phenotype; animal; metabolism; animals; mice; animal tissue; dna damage; cancer susceptibility; breast cancer; nuclear protein; protein dna binding; animal experiment; animal model; genetic transcription; transcription, genetic; breast neoplasms; wild type; oncogenes; gene expression regulation; oncogene; gene expression regulation, neoplastic; adverse outcome; genomic instability; breast tumor; breast epithelium; innate immunity; immunity, innate; dna structure; cancer tissue; immune response gene; metastatic breast cancer; breast carcinogenesis; chromatin assembly and disassembly; mre11 complex; mre11a protein, mouse; interferons; female; article; mutant mouse strain; organoids; organoid; immune signaling; breast tissue; double strand break repair protein mre11; interferon-stimulated gene; mre11 homologue protein; interferon inducible gene 205; interferon stimulated gene; mammary organoid |
| Journal Title: | Genes and Development |
| Volume: | 38 |
| Issue: | 21-24 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2024-11-01 |
| Start Page: | 979 |
| End Page: | 997 |
| Language: | English |
| DOI: | 10.1101/gad.351455.123 |
| PUBMED: | 39455282 |
| PROVIDER: | scopus |
| PMCID: | PMC11610935 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is John Petrini -- Source: Scopus |
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