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Division of Gynecologic Oncology, Department of Surgery [A. H.], Developmental Chemotherapy Service, Department of Medicine [G. H., D. R. S.], and Department of Epidemiology and Biostatistics [E. S. V.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021
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.
1 Supported by a generous grant from Metropolitan Life.
2 To whom requests for reprints should be addressed, at Developmental Chemotherapy Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.
Received 11/19/97. Accepted 1/28/98.
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