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 (Mre11^ATLD1/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 Mre11^ATLD1/ATLD1 organoids exhibited an elevated interferon-stimulated gene (ISG) signature and sustained changes in chromatin accessibility. This Mre11^ATLD1/ATLD1 phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation of Ifi205 in Mre11^ATLD1/ATLD1 organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed in WT. Implantation of Mre11^ATLD1/ATLD1 organoids and activation of the oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implanted Ifi205^−/− Mre11^ATLD1/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.

中文翻译：

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慢性干扰素刺激的基因转录促进癌基因诱导的乳腺癌


MRE11 复合体（包括 MRE11、RAD50 和 NBS1）是维持基因组稳定性不可或缺的一部分。我们之前表明，亚形性 Mre11 突变小鼠品系 （Mre11^ATLD1/ATLD1） 对癌基因诱导的乳腺癌高度敏感。在这里，我们使用乳腺类器官系统来检查哪些 MRE11 依赖性反应是肿瘤抑制的。我们发现 Mre11^ATLD1/ATLD1 类器官表现出较高的干扰素刺激基因 （ISG） 特征和染色质可及性的持续变化。这种 Mre11^ATLD1/ATLD1 表型依赖于核先天免疫传感器 IFI205 的 DNA 结合。Mre11^ATLD1/ATLD1 类器官中 Ifi205 的消融使基线和癌基因诱导的染色质可及性模式恢复到 WT 中观察到的水平。Mre11^ATLD1/ATLD1 类器官的植入和癌基因的激活导致侵袭性转移性乳腺癌。这种结果在植入的 Ifi205^-/-Mre11^ATLD1/ATLD1 类器官中是相反的。这些数据揭示了先天免疫信号转导与乳腺上皮肿瘤发展之间的联系。鉴于在基因组不稳定综合征背景下出现的大量异常 DNA 结构，数据进一步表明，这些背景下的癌症易感性可能部分归因于慢性先天免疫转录程序。