Kennedy Richard D, Quinn Jennifer E, Mullan Paul B, Johnston Patrick G, Harkin D Paul
Department of Oncology, Cancer Research Centre, The Queen's University of Belfast, Northern Ireland.
J Natl Cancer Inst. 2004 Nov 17;96(22):1659-68. doi: 10.1093/jnci/djh312.
Germline mutations of the BRCA1 gene account for approximately 5% of breast and ovarian cancer cases, and lower than normal BRCA1 expression or function may be an important contributing factor in sporadic cancers. The major role of BRCA1 is to respond to DNA damage by participating in cellular pathways for DNA repair, mRNA transcription, cell cycle regulation, and protein ubiquitination. Because most chemotherapeutic agents function by directly or indirectly damaging DNA, the role of BRCA1 as a regulator of chemotherapy-induced DNA damage has been the subject of an increasing number of investigations. We review published preclinical and clinical evidence that the level of BRCA1 function in an individual patient's tumor can guide the choice of chemotherapeutic agents for breast and ovarian cancer. We conclude that a loss of BRCA1 function is associated with sensitivity to DNA-damaging chemotherapy and may also be associated with resistance to spindle poisons. We recommend that prospective clinical studies investigating the role of BRCA1 in the response to chemotherapy be conducted.
BRCA1基因的种系突变约占乳腺癌和卵巢癌病例的5%，而BRCA1表达或功能低于正常水平可能是散发性癌症的一个重要促成因素。BRCA1的主要作用是通过参与DNA修复、mRNA转录、细胞周期调控和蛋白质泛素化的细胞途径来应对DNA损伤。由于大多数化疗药物通过直接或间接损伤DNA发挥作用，BRCA1作为化疗诱导的DNA损伤调节剂的作用已成为越来越多研究的主题。我们综述了已发表的临床前和临床证据，即个体患者肿瘤中BRCA1的功能水平可指导乳腺癌和卵巢癌化疗药物的选择。我们得出结论，BRCA1功能丧失与对DNA损伤化疗的敏感性相关，也可能与对纺锤体毒素的耐药性相关。我们建议开展前瞻性临床研究，调查BRCA1在化疗反应中的作用。
