BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression

The breast and ovarian cancer susceptibility gene product BRCA1 has been re ported to be expressed in a cell cycle-dependent manner; possess transcript ional activity; associate with several proteins, including the p53 tumor su ppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1 ) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase ac cumulation, High d ensity cDNA array screening of colon, lung and breast cancer cells identifi ed several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle contro l, Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to m odulate the expression of genes and function of proteins involved in cell c ycle control and DNA damage response pathways.