BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II).
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.
Husain
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Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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Venkatraman
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Spriggs
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D001943:Breast Neoplasms; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1 / Q000235:genetics*; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D012334:RNA, Neoplasm; D002945:Cisplatin