Mre11 复合体（包括 Mre11、Rad50、Nbs1）对于维持基因组稳定性至关重要。我们之前表明，Mre11 亚型突变小鼠品系（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 依赖性反应具有肿瘤抑制作用。我们发现 Mre11 ATLD1/ATLD1 类器官表现出较高的干扰素刺激基因 (ISG) 特征以及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 的消融恢复了 WT 中观察到的基线和癌基因诱导的染色质可及性模式。 Mre11 ATLD1/ATLD1 类器官的植入和癌基因的激活导致了侵袭性转移性乳腺癌。这一结果在植入的 Ifi205 -/- Mre11 ATLD1/ATLD1 类器官中得到逆转。这些数据揭示了先天免疫信号传导与乳腺上皮肿瘤抑制之间的联系。鉴于基因组不稳定综合征背景下出现大量异常 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强直的先天免疫转录程序。

The Mre11 complex (comprising Mre11, Rad50, 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 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 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.