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BRCA1 Pathway Function in Basal-Like Breast Cancer Cells

机译：基底细胞样乳腺癌细胞中的BRCA1通路功能

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Sporadic basal-like cancers (BLCs) are a common subtype of breast cancer that share multiple biological properties with BRCA1-mutated breast tumors. Despite being BRCA1+/+, sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers, because they are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway(s) in which BRCA1 plays a major role. The role of BRCA1 in the repair of double-strand DNA breaks by homologous recombination (HR) is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. Therefore, it is suspected that sporadic BLCs exhibit a defect in HR. To test this hypothesis, multiple DNA damage repair assays focused on several types of repair were performed on a group of cell lines classified as sporadic BLCs and on controls. The sporadic BLC cell lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks, another BRCA1 function. These results provide insight into why clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors, which require an HR defect for efficacy, have been unsuccessful in sporadic BLCs, unlike cisplatin, which elicits DNA damage that requires stalled fork repair and has shown efficacy in sporadic BLCs.
机译：散发性基底膜样癌（BLC）是乳腺癌的常见亚型，与BRCA1突变的乳腺癌具有多种生物学特性。尽管散发性BLC尽管是BRCA1 + / + ，但仍被广泛认为是BRCA1突变的乳腺癌的表型，因为它们被假定表现为BRCA1功能缺陷或BRCA1发挥作用的途径的破坏。一个重要的角色。 BRCA1在通过同源重组（HR）修复双链DNA断裂中的作用是人们对其功能的最佳理解，也是最常涉及BRCA1乳腺癌抑制的功能。因此，怀疑零星的BLC表现出HR缺陷。为了检验该假设，对分类为零星BLC的一组细胞系和对照进行了针对几种修复类型的多种DNA损伤修复测定。零星的BLC细胞系未能表现出明显的HR缺陷。而是，它们在停滞的复制叉（BRCA1的另一个功能）的修复中表现出缺陷。这些结果为为什么需要散发性BLC的聚（ADP-核糖）聚合酶（PARP）抑制剂的临床试验为何未能成功在散发性BLC中失败提供了见解，与顺铂不同，顺铂引起了DNA损伤，需要进行停滞的叉修复并具有在散发性BLC中显示出疗效。

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