Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene
Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer: MRE11 as a candidate familial cancer-predisposing gene
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DOI：
10.1016/j.molonc.2008.09.007
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发表时间：
2008-12-01
影响因子：
6.6
通讯作者：
Bartek, Jiri
中科院分区：
文献类型：
--
作者：
Bartkova, Jirina;Tommiska, Johanna;Bartek, Jiri
MRE 11、RAD 50和NBS 1基因编码MRE 11-RAD 50-NBS 1（MRN）复合物的蛋白质，该复合物对于正确维持基因组完整性和肿瘤抑制至关重要;然而，其癌症易感缺陷的程度和影响以及潜在的临床价值仍有待确定。在这里，我们报告说，在大约1000个乳腺癌的大系列中，大约3%，7%和10%的肿瘤分别显示出异常减少的蛋白质表达的RAD 50，MRE 11和NBS 1。这种缺陷在ER/PR/ERBB 2三阴性和高级别肿瘤中更常见，在家族性（特别是BRCA 1/BRCA 2相关）而不是散发性病例中，NBS 1缺陷与较短的患者生存期相关。BRCA 1相关和ER/PR/ERBB 2三阴性肿瘤也显示出组成性活性DNA损伤信号传导（γ H2 AX）和p53畸变的高发生率。对来自非BRCA 1/2乳腺癌家族的8名患者的RAD 50、MRE 11和NBS 1基因进行测序，这些患者的肿瘤显示所有三种MRN复合物蛋白同时减少/丢失，发现MRE 11中存在两种种系突变：错义突变R202 G和截短突变R633 STOP（R633 X）。突变MRE 11的细胞培养模型的基因转移和蛋白质分析暗示了MRN复合物蛋白（包括NBS 1）之间的各种不稳定模式，其丰度通过野生型MRE 11的重新表达而恢复。我们认为，生殖系突变使MRE 11有资格成为非BRCA 1/2家族中一个新的候选乳腺癌易感基因。我们的数据对DNA损伤反应作为内在抗癌屏障的概念有影响，其各种成分在癌症进展过程中变得失活，并且也代表了迄今为止发现的大部分乳腺癌易感基因。(C)2008年欧洲生化学会联合会。Elsevier B. V.出版，保留所有权利。
The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11-RAD50-NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer-predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple-negative and higher-grade tumours, among familial (especially BRCA1/BRCA2-associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients' survival. The BRCA1-associated and ER/PR/ERBB2 triple-negative tumours also showed high incidence of constitutively active DNA damage signalling (gamma H2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non-BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN-complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re-expression of wild-type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non-BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti-cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.