Hexiao Wang, Claudia Canasto-Chibuque, Jun Hyun Kim, Marcel Hohl, Christina Leslie, Jorge S. Reis-Filho, John H.J. Petrini
{"title":"Chronic interferon-stimulated gene transcription promotes oncogene-induced breast cancer","authors":"Hexiao Wang, Claudia Canasto-Chibuque, Jun Hyun Kim, Marcel Hohl, Christina Leslie, Jorge S. Reis-Filho, John H.J. Petrini","doi":"10.1101/gad.351455.123","DOIUrl":null,"url":null,"abstract":"The MRE11 complex (comprising MRE11, RAD50, and NBS1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic <em>Mre11</em> mutant mouse strain (<em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup>) 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 <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> organoids exhibited an elevated interferon-stimulated gene (ISG) signature and sustained changes in chromatin accessibility. This <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation of <em>Ifi205</em> in <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed in WT. Implantation of <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> organoids and activation of the oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implanted <em>Ifi205</em><sup>−/−</sup> <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> 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.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"194 1","pages":""},"PeriodicalIF":7.5000,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genes & development","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1101/gad.351455.123","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Genes & Development is a research journal published in association with The Genetics Society. It publishes high-quality research papers in the areas of molecular biology, molecular genetics, and related fields. The journal features various research formats including Research papers, short Research Communications, and Resource/Methodology papers.
Genes & Development has gained recognition and is considered as one of the Top Five Research Journals in the field of Molecular Biology and Genetics. It has an impressive Impact Factor of 12.89. The journal is ranked #2 among Developmental Biology research journals, #5 in Genetics and Heredity, and is among the Top 20 in Cell Biology (according to ISI Journal Citation Reports®, 2021).