Husain A, He G, Venkatraman E S, Spriggs D R
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 1998 Mar 15;58(6):1120-3.
We sought to identify novel genes associated with cis-diamminedichloroplatinum(II) (CDDP) resistance, and by differential display analysis, we found that the human breast and ovarian cancer susceptibility gene BRCA1 was overexpressed in CDDP-resistant MCF-7 cells. A recent report that BRCA1 and human Rad51 colocalize in S-phase cells suggests a role for BRCA1 in DNA damage repair. We hypothesized that BRCA1 plays a role in DNA damage repair-mediated CDDP resistance. In CCDP-resistant variants of breast and ovarian carcinoma cell lines, MCF-7 CDDP/R and SKOV-3 CDDP/R, we found increased levels of BRCA1 protein, and we determined that the SKOV-3 CDDP/R cell line is significantly more proficient at DNA damage repair. Antisense inhibition of BRCA1 in this cell line resulted in an increased sensitivity to CDDP, a decreased proficiency of DNA repair, and an enhanced rate of apoptosis. These data support the hypothesis that BRCA1 is a gene involved in DNA damage repair.
我们试图鉴定与顺二氯二氨铂（II）（CDDP）耐药相关的新基因，通过差异显示分析，我们发现人类乳腺癌和卵巢癌易感基因BRCA1在耐CDDP的MCF-7细胞中过表达。最近有报道称BRCA1与人Rad51在S期细胞中共定位，这表明BRCA1在DNA损伤修复中发挥作用。我们推测BRCA1在DNA损伤修复介导的CDDP耐药中起作用。在乳腺癌和卵巢癌细胞系的耐CCDP变体MCF-7 CDDP/R和SKOV-3 CDDP/R中，我们发现BRCA1蛋白水平升高，并且我们确定SKOV-3 CDDP/R细胞系在DNA损伤修复方面明显更熟练。在该细胞系中对BRCA1进行反义抑制导致对CDDP的敏感性增加、DNA修复能力下降以及凋亡率提高。这些数据支持BRCA1是参与DNA损伤修复的基因这一假说。
