J Clin Invest. 2024 Apr 1;134(7):e179325. doi: 10.1172/JCI179325.
While breast cancer 2 (BRCA2) loss of heterozygosity (LOH) promotes cancer initiation, it can also induce death in nontransformed cells. In contrast, mismatch repair gene mutL homolog 1 (MLH1) is a tumor-suppressor gene that protects cells from cancer development through repairing mismatched base pairs during DNA mismatch repair (MMR). Sengodan et al., in this issue of the JCI, reveal an interplay between the 2 genes: MLH1 promoted the survival of BRCA2-deficient cells independently of its MMR function. MLH1 protected replication forks from degradation, while also resolving R-loops, thereby reducing genomic instability. Moreover, MLH1 expression was regulated directly by estrogen, shedding light into the hormone-responsive nature of many BRCA2 mutant breast cancers. These results provide important insight into the genetics that drive the initiation of BRCA2-mutated breast cancers.
虽然乳腺癌 2 号基因（BRCA2）杂合性丢失（LOH）会促进癌症的发生，但它也会导致非转化细胞死亡。相比之下，错配修复基因 mutL 同源物 1（MLH1）是一种肿瘤抑制基因，它通过在 DNA 错配修复（MMR）过程中修复错配碱基对，从而保护细胞免受癌症的发展。Sengodan 等人在本期《临床检查杂志》中揭示了这两个基因之间的相互作用：MLH1 通过独立于其 MMR 功能促进 BRCA2 缺陷细胞的存活。MLH1 保护复制叉免受降解，同时还能解决 R 环，从而减少基因组不稳定性。此外，MLH1 的表达受雌激素的直接调控，这揭示了许多 BRCA2 突变型乳腺癌的激素反应性质。这些结果为驱动 BRCA2 突变型乳腺癌发生的遗传学提供了重要的见解。
