Aleskandarany Mohammed, Caracappa Daniela, Nolan Christopher C, Macmillan R Douglas, Ellis Ian O, Rakha Emad A, Green Andrew R
Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK,
Breast Cancer Res Treat. 2015 Feb;150(1):81-90. doi: 10.1007/s10549-015-3306-6. Epub 2015 Feb 19.
Cells have stringent DNA repair pathways that are specific for each different set of DNA lesions which is accomplished through the integration of complex array of proteins. However, BRCA-mutated breast cancer (BC) has defective DNA repair mechanisms. This study aims to investigate differential expression of a large panel of DNA repair markers to characterise DNA repair mechanisms in BRCA-associated tumours compared to sporadic tumours in an attempt to characterise these tumours in routine practice. Immunohistochemistry and tissue microarray technology were applied to a cohort of clinically annotated series of sporadic (n = 1849), BRCA1-mutated (n = 48), and BRCA2-mutated (n = 27) BC. The following DNA damage response (DDR) markers are used; BRCA1, BRCA2, RAD51, Ku70/Ku80, BARD, PARP1 (cleaved), PARP1 (non-cleaved), and P53 in addition to basal cytokeratins, ER, PR, and HER2. A significant proportion of BRCA1 tumours were positive for PARP1 (non-cleaved), and negative for BARD1 and RAD51 compared with sporadic BC. BRCA2 tumours were significantly positive for PARP1 (non-cleaved) compared with sporadic tumours. RAD51 was significantly higher in BRCA1 compared with BRCA2 tumours (p = 0.005). When BRCA1/2 BCs were compared to triple-negative (TN) sporadic tumours of the studied DDR proteins, BARD1 (p < 0.001), PARP1 (non-cleaved) (p < 0.001), and P53 (p = 0.002) remained significantly different in BRCA1/2 tumours compared with TN BC. DNA repair markers showed differential expression in BRCA-mutated tumours, with a substantial degree of disruption of DNA repair pathways in sporadic BC especially TN BC. DNA double-strand break (DSB) repair is assisted by PARP1 expression in BRCA-mutated tumours, whereas the loss of DSB repair via RAD51 is predominant in BRCA1 rather than BRCA2 BC.
细胞拥有严格的DNA修复途径，这些途径针对每一组不同的DNA损伤具有特异性，这是通过一系列复杂蛋白质的整合来实现的。然而，BRCA突变的乳腺癌（BC）具有缺陷的DNA修复机制。本研究旨在调查大量DNA修复标志物的差异表达，以表征BRCA相关肿瘤与散发性肿瘤相比的DNA修复机制，试图在常规实践中对这些肿瘤进行特征描述。免疫组织化学和组织微阵列技术应用于一组临床注释的散发性（n = 1849）、BRCA1突变（n = 48）和BRCA2突变（n = 27）的BC系列。除了基底细胞角蛋白、雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）外，还使用了以下DNA损伤反应（DDR）标志物：BRCA1、BRCA2、RAD51、Ku70/Ku80、BARD1、聚（ADP-核糖）聚合酶1（PARP1，裂解型）、PARP1（非裂解型）和P53。与散发性BC相比，相当一部分BRCA1肿瘤的PARP1（非裂解型）呈阳性，而BARD1和RAD51呈阴性。与散发性肿瘤相比，BRCA2肿瘤的PARP1（非裂解型）显著呈阳性。与BRCA2肿瘤相比，RAD51在BRCA1肿瘤中显著更高（p = 0.005）。当将BRCA1/2 BC与所研究的DDR蛋白的三阴性（TN）散发性肿瘤进行比较时，BRCA1/2肿瘤中的BARD1（p < 0.001）、PARP1（非裂解型）（p < 0.001）和P53（p = 0.002）与TN BC相比仍有显著差异。DNA修复标志物在BRCA突变的肿瘤中表现出差异表达，散发性BC尤其是TN BC中DNA修复途径存在大量破坏。在BRCA突变的肿瘤中，PARP1的表达有助于DNA双链断裂（DSB）修复，而通过RAD51的DSB修复缺失在BRCA1 BC中比在BRCA2 BC中更为突出。
