Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 
have been linked to the development of breast cancer, ovarian cancer, and other 
malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may 
function in the sensing and/or repair of DNA damage. To investigate this 
possibility, we determined the effects of various DNA-damaging agents and other 
cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other 
human breast cancer cell lines. We found that several agents, including 
adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin 
(a topoisomerase I inhibitor), and ultraviolet radiation induced significant 
decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 
mRNAs were observed within 6-12 h after treatment with adriamycin and persisted 
for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; 
but these decreases required several days. U.V. radiation induced dose-dependent 
down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both 
mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. 
Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed 
at doses that yielded relatively little cytotoxicity and little or no apoptotic 
DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and 
time-dependent alterations in the cell cycle distribution; but these alterations 
did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA 
levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels 
was correlated with p53 functional status. MCF-7 cells transfected with a 
dominant negative mutant p53 (143 val-->ala) required at least tenfold higher 
doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental 
MCF-7 cells or control-transfected MCF-7 clones. These results suggest that 
BRCA1 and BRCA2 may play roles in the cellular response to DNA-damaging agents 
and that there may be a p53-sensitive component to the regulation of BRCA1 and 
BRCA2 mRNA expression.