BRCA1 Pathway Function in Basal-Like Breast Cancer Cells
BRCA1 Pathway Function in Basal-Like Breast Cancer Cells
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DOI：
10.1128/mcb.01646-13
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发表时间：
2014-10-01
影响因子：
5.3
通讯作者：
Livingston, David M.
中科院分区：
文献类型：
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作者：
Hill, Sarah J.;Clark, Allison P.;Livingston, David M.
散发性基底样癌（blc）是一种常见的乳腺癌亚型，与brca1突变的乳腺肿瘤具有多种生物学特性。尽管是BRCA1(+/+)，散发性blc被广泛认为是BRCA1突变乳腺癌的表型，因为它们被假设表现为BRCA1功能缺陷或BRCA1起主要作用的途径的破坏。BRCA1在同源重组（HR）修复双链DNA断裂中的作用是其最被了解的功能，也是最常与BRCA1乳腺癌抑制有关的功能。因此，我们怀疑散发性blc在HR中表现出缺陷。为了验证这一假设，对一组被分类为散发性blc和对照组的细胞系进行了多种DNA损伤修复试验，重点研究了几种类型的修复。散发性BLC细胞系没有表现出明显的HR缺陷。相反，它们在修复停滞的复制分叉（BRCA1的另一种功能）方面表现出缺陷。这些结果揭示了为什么聚（adp -核糖）聚合酶（PARP）抑制剂（需要HR缺陷才能起作用）的临床试验在散发性blc中不成功，而顺铂会引起DNA损伤，需要暂停叉修复，并在散发性blc中显示出疗效。
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.