UGT2B7基因多态性对表柔比星个体用药差异的影响及机制研究

表柔比星是乳腺癌新辅助化疗常用的蒽环类药物之一，但由于缺乏有效的预后预测指标，其疗效参差不齐，故找出影响表柔比星疗效的关键因子对于乳腺癌患者的个体化用药极其重要。UGT2B7是表柔比星在体内的主要代谢酶，课题组先前小样本量预实验结果提示UGT2B7 211G>T和802C>T可降低表柔比星的阳性反应率。为了进一步证实此结果，本课题拟继续收集中国汉族女性局部晚期乳腺癌受试者的外周血标本，通过基因多态性检测，分析UGT2B7 SNPs及单倍型对表柔比星化疗疗效和毒性差异的影响；并利用杆状病毒表达系统和双荧光素酶系统，分析UGT2B7突变体重组酶对表柔比星代谢及酶转录活性的影响；在裸鼠移植乳腺癌的模型上，通过siRNA干扰和慢病毒过表达UGT2B7基因，观察UGT2B7表达变化对表柔比星化疗敏感性的影响。通过本研究阐明表柔比星个体用药差异的主要原因，为表柔比星化疗疗效提供可靠的预后预测指标。

Epirubicin is one of the anthracyclines frequently used in neoadjuvant chemotherapy of breast cancer. However, significant variable responses of epirubicin have been observed in the clinical treatment. Uridine diphosphate-glucuronosyltransferases (UGT) 2B7 involves in the metabolism of epirubicin. Our previous study implied that UGT2B7 genetic polymorphisms reduced the efficacy of epirubicin-based chemotherapy. This project aims to verify the previous finding, by collecting a large group of blood samples from patients (locally advanced invasive breast cancer) of Chinese Han population. Firstly, the UGT2B7 genetic polymorphisms are genotyped, and the efficiency and toxicity of epirubicin-based chemotherapy are compared between different genotypes and haplotypes. Secondly, in order to confirm the effects of genetic polymorphisms in UGT2B7 gene on the biotransformation of epirubicin, baculovirus-insect cell expression system and dual-luciferase reporter assay system are studied in vitro. Finally, small interfrence RNA (siRNA)-mediated sliencing or lentivirus-mediated overexpressing of UGT2B7 is established. Then the impact of UGT2B7 expression on the treatment outcome of epirubicin chemotherapy is evaluated by human breast cancer xenograft in nude mice. Our findings may provide the genetic polymorphisms of UGT2B7. This information should be included in future research that develop and test new classification systems for epirubicin-based neoadjuvant chemotherapy treatment in patients with breast cancer.