Clinical and biological significance of RAD51 expression in breast cancer: a key DNA damage response protein
Clinical and biological significance of RAD51 expression in breast cancer: a key DNA damage response protein
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DOI：
10.1007/s10549-016-3915-8
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发表时间：
2016-08-01
影响因子：
3.8
通讯作者：
Rakha, Emad A.
中科院分区：
文献类型：
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作者：
Alshareeda, Alaa Tarig;Negm, Ola H.;Rakha, Emad A.
DNA损伤反应受损(DDR)可能在乳腺癌(BC)的发病机制中起重要作用。RAD51在DNA双链断裂修复中起关键作用。在这项研究中，我们旨在评估RAD51表达的生物学和临床意义与不同分子类型的BC和患者的预后相关。采用免疫组织化学方法对1184例早期侵袭性BC中RAD51的表达进行了评价。来自已知BRCA1胚系突变患者的BC病例的子集被包括作为对照组。结果与临床病理和分子参数及患者预后相关。用反相蛋白质阵列(RPPA)检测一组细胞中RAD51蛋白的表达水平。RAD51表达于癌细胞的胞核(N)和胞浆(C)。RAD51亚细胞共定位表型与临床病理特征和患者预后显著相关。细胞质表达(RAD51C(+))和核表达缺失(RAD51N-)与侵袭性行为特征相关，包括较大的肿瘤大小、高级别、淋巴结转移、基底样和三阴性表型，以及包括BRCA1在内的关键DDR生物标志物的异常表达。所有BRCA1突变肿瘤均为RAD51C(+)/N-表型。RPPA证实了IHC结果，并根据ER表达和BRCA1状态显示RAD51在细胞系中的差异表达。RAD51N+和RAD51C(+)肿瘤分别与乳腺癌特异性生存期(BCS)较长和较短相关。RAD51N+是较长BCS的独立预测因子(P<；0.0001)。侵袭性BC患者缺乏RAD51核表达与不良的预后参数和较短的生存期有关。RAD51亚细胞定位与临床病理特征、分子亚型和患者预后的显著相关性表明，DDR蛋白在胞核和胞浆之间的转运可能在BC的发生发展中发挥作用。
Impaired DNA damage response (DDR) may play a fundamental role in the pathogenesis of breast cancer (BC). RAD51 is a key player in DNA double-strand break repair. In this study, we aimed to assess the biological and clinical significance of RAD51 expression with relevance to different molecular classes of BC and patients' outcome. The expression of RAD51 was assessed immunohistochemically in a well-characterised annotated series (n = 1184) of early-stage invasive BC with long-term follow-up. A subset of cases of BC from patients with known BRCA1 germline mutations was included as a control group. The results were correlated with clinicopathological and molecular parameters and patients' outcome. RAD51 protein expression level was also assayed in a panel of cell lines using reverse phase protein array (RPPA). RAD51 was expressed in the nuclei (N) and cytoplasm (C) of malignant cells. Subcellular co-localisation phenotypes of RAD51 were significantly associated with clinicopathological features and patient outcome. Cytoplasmic expression (RAD51C(+)) and lack of nuclear expression (RAD51 N-) were associated with features of aggressive behaviour, including larger tumour size, high grade, lymph nodal metastasis, basal-like, and triple-negative phenotypes, together with aberrant expression of key DDR biomarkers including BRCA1. All BRCA1-mutated tumours had RAD51C(+)/N- phenotype. RPPA confirmed IHC results and showed differential expression of RAD51 in cell lines based on ER expression and BRCA1 status. RAD51 N+ and RAD51C(+) tumours were associated with longer and shorter breast cancer-specific survival (BCSS), respectively. The RAD51 N+ was an independent predictor of longer BCSS (P < 0.0001). Lack of RAD51 nuclear expression is associated with poor prognostic parameters and shorter survival in invasive BC patients. The significant associations between RAD51 subcellular localisation and clinicopathological features, molecular subtype and patients' outcome suggest that the trafficking of DDR proteins between the nucleus and cytoplasm might play a role in the development and progression of BC.