Department of Pathology, Hacettepe University, Ankara, Turkey.
Breast Cancer Res Treat. 2011 Sep;129(2):421-32. doi: 10.1007/s10549-010-1248-6. Epub 2010 Nov 11.
Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.
landmark 研究已关注于 DNA 损伤检查点和相关修复功能在癌前和肿瘤细胞中的状态在癌症发展中的重要性，并且修复途径的抑制剂正在临床试验中用于治疗三阴性乳腺癌。癌症异质性表明，特定的癌症亚型将具有不同的 DNA 损伤存活机制，这取决于生物学背景。在这项研究中，我们研究了与临床特征相关的乳腺癌亚型中与 DNA 损伤反应 (DDR) 相关的蛋白状态；检查了 479 例乳腺癌中 DDR 蛋白 γH2AX、BRCA1、pChk2 和 p53、DNA 损伤敏感肿瘤抑制因子 Fhit 和 Wwox 以及 Wwox 相互作用蛋白 Ap2α、Ap2γ、ErbB4 的表达情况，并评估了蛋白、肿瘤亚型和临床特征之间的相关性。在多变量模型中，三阴性癌症显示出明显减少的 Fhit 和 Wwox，增加的 p53 和 Ap2γ 蛋白表达，并且比其他亚型肿瘤更有可能表现出两个或更多 DDR 相关蛋白的异常表达。无病生存与亚型、Fhit 和膜 ErbB4 表达水平以及多个 DDR 相关蛋白的异常表达有关。这些结果表明，在三阴性癌症亚组中定义特定的 DNA 修复和检查点缺陷可能会确定新的治疗靶点。Wwox 及其相互作用蛋白 ErbB4 的表达在转移性组织与匹配的原发性组织相比显著降低，这表明 Wwox 信号通路的丧失导致淋巴结转移，可能是通过允许已经从基底膜分离的肿瘤细胞存活，正如 Wwox 在卵巢癌扩散中的作用所提出的那样。
