BRCA1基因相关的DNA修复通路异常与三阴乳腺癌化疗药物选择的关系

Association of BRCA1-related DNA repair genetic variations and high incidence of metastasis in triple-negative breast cancer

三阴乳腺癌以雌激素受体(estrogen receptor,ER)、孕激素受体(progestogen receptor,PR)以及Her-2阴性为特征,临床表现为组织分化差,术后易出现局部复发和远处转移,而且脏器比骨骼更容易发生转移。因对内分泌治疗和以Her-2为靶向分子的治疗无效,化疗成为治疗方案中的主体。与其他类型乳腺癌比较,三阴乳腺癌患者与乳腺基底细胞样癌和乳癌基因1(BRCA1)相关性乳腺癌在表型和分子生物学水平方面具有很多共性。不同个体DNA损伤修复能力的差异和乳腺癌的发病密切相关。BRCA1以及相关的DNA修复通路中的不同基因,如BRCA2、ATM、RAD51和CHEK2对维护基因组稳定性方面有重要作用。因此,三阴乳腺癌患者BRCA1相关的DNA修复通路异常而导致DNA修复能力异常,影响了其对化疗药物的敏感性,进而可能促进了高转移特性的形成。导致三阴乳腺癌重要脏器转移高发的原因,是肿瘤本身的转移相关基因异常的内因所致,还是对所接受的治疗耐药而使肿瘤细胞处于逃逸状态而引起,目前尚不明确。因此本文对BRCA1相关的DNA修复通路异常与三阴乳腺癌高转移之间的关系进行综述。

Triple-negative breast cancer is defined by the absence of expression of oestrogen, progesterone, and Her-2 receptors. The clinicopathological characteristics include： higher histological grades, earlier relapse with worse prognosis, and a higher incidence of visceral metastases than bone metastases. Since it has no response to hormone treatment and targeted therapy for Her-2, chemotherapy became the main therapy. In addition, it may have a relationship with basal-like breast cancer and BRCAl-related breast cancer on the phenotype and molecular level. Inter-individual variations in DNA damage and repair have been associated with an increased risk of breast cancer. BRCA1 together with its associated genes such as BRCA2, ATM, RAD51 and CHEK2 play vital roles in different DNA repair pathways to preserve genome stability. Therefore variations of BRCA1 and its associated genes in multiple repair pathways may result in reduced DNA repair capacity and altered sensitivity to cytotoxic chemotherapeutic agents, which could promote incidence of distant metastases. Reduced DNA repair capacity and dysfunctional BRCA1 pathway in triple-negative breast cancer have been reported, however the detailed mechanisms are still unknown. Do the genetic variations of tumor cells or resistance of tumor cells to therapeutic drugs play the dominant role in high incidence of metastases in patients with triple-negative breast cancer？ In this review, the association of dysfunctional BRCA/-related DNA repair pathways with high incidence of metastasis in triple-negative breast cancer would be introduced.