Division of Breast and Endocrine Surgery, Department of Surgery, St, Marianna University School of Medicine, Kawasaki, Japan.
Breast Cancer Res. 2010;12(2):R17. doi: 10.1186/bcr2486. Epub 2010 Mar 5.
Various agents used in breast cancer chemotherapy provoke DNA double-strand breaks (DSBs). DSB repair competence determines the sensitivity of cells to these agents whereby aberrations in the repair machinery leads to apoptosis. Proteins required for this pathway can be detected as nuclear foci at sites of DNA damage when the pathway is intact. Here we investigate whether focus formation of repair proteins can predict chemosensitivity of breast cancer.
Core needle biopsy specimens were obtained from sixty cases of primary breast cancer before and 18-24 hours after the first cycle of neoadjuvant epirubicin plus cyclophosphamide (EC) treatment. Nuclear focus formation of DNA damage repair proteins was immunohistochemically analyzed and compared with tumor response to chemotherapy.
EC treatment induced nuclear foci of gammaH2AX, conjugated ubiquitin, and Rad51 in a substantial amount of cases. In contrast, BRCA1 foci were observed before treatment in the majority of the cases and only decreased after EC in thirteen cases. The presence of BRCA1-, gammaH2AX-, or Rad51-foci before treatment or the presence of Rad51-foci after treatment was inversely correlated with tumor response to chemotherapy. DNA damage response (DDR) competence was further evaluated by considering all four repair indicators together. A high DDR score significantly correlated with low tumor response to EC and EC + docetaxel whereas other clinicopathological factors analyzed did not.
High performing DDR focus formation resulted in tumor resistance to DNA damage-inducing chemotherapy. Our results suggested an importance of evaluation of DDR competence to predict breast cancer chemosensitivity, and merits further studying into its usefulness in exclusion of non-responder patients.
各种用于乳腺癌化疗的药物都会引起 DNA 双链断裂（DSB）。DSB 修复能力决定了细胞对这些药物的敏感性，而修复机制的异常会导致细胞凋亡。当该途径完整时，用于该途径的蛋白质可以作为核焦点在 DNA 损伤部位检测到。在此，我们研究修复蛋白的焦点形成是否可以预测乳腺癌的化疗敏感性。
在新辅助表柔比星加环磷酰胺（EC）治疗的第一个周期前和 18-24 小时后，从 60 例原发性乳腺癌患者中获得核心针活检标本。用免疫组化方法分析核损伤修复蛋白的焦点形成，并与化疗的肿瘤反应进行比较。
EC 治疗在大量病例中诱导了γH2AX、缀合泛素和 Rad51 的核焦点。相比之下，BRCA1 焦点在大多数病例中在治疗前存在，只有在 13 例中在 EC 后才减少。治疗前存在 BRCA1、γH2AX 或 Rad51 焦点，或治疗后存在 Rad51 焦点与对化疗的肿瘤反应呈负相关。通过同时考虑所有四个修复指标，进一步评估了 DNA 损伤反应（DDR）能力。高 DDR 评分与 EC 和 EC+多西紫杉醇的低肿瘤反应显著相关，而分析的其他临床病理因素则没有。
高 DDR 焦点形成导致肿瘤对 DNA 损伤诱导的化疗产生耐药性。我们的结果表明，评估 DDR 能力以预测乳腺癌化疗敏感性的重要性，值得进一步研究其在排除非反应性患者中的有用性。
