Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors

Predisposition to breast cancer has been attributed to mutant BRCA1 alleles whereas no BRCA1 mutation has been described yet in sporadic breast tumours. As an initial characterization of the regulation and function of the BRCA1 gene in sporadic breast cancer, we have compared the expression of BRCA1 in thirty-five paired tumour specimens versus their corresponding adjacent normal tissue. We found two- to five-fold reduced BRCA1 expression levels in tumour specimens as compared to normal tissue. Decreased BRCA1 expression was significantly associated with loss of heterozygosity (LOH) at the BRCA1 region, as well as with negative estrogen receptor (ER) status. Our results offer an alternative explanation of how BRCA1 could play an important role in sporadic breast cancer, not via mutations in coding sequences but due to transcriptional disregulation. Decreased BRCA1 mRNA may be caused due to loss of gene copies, deletions of regulatory elements in the BRCA1 promoter or failure of transcriptional regulation by estrogen receptors. We also investigated possible relationships between BRCA1, p53, mdm-2 and p21(WAF1/CIP1) at the expression level. p53 expression was unaffected in almost all the specimens, mdm-2 was overexpressed in 18/35 specimens while 21/35 overexpressed p21. Samples exhibiting reduced BRCA1 levels simultaneously overexpressed both p21 and mdm-2, showing that BRCA1, at certain levels, even reduced up to 2.7-fold, is functional and sufficient to upregulate p21, when p53 activity is inhibited by its negative regulator, the mdm-2. On the contrary, specimens exhibiting more than 2.7-fold reduced BRCA1 levels, overexpressed p21 while mdm-2 expression was normal, allowing us to speculate that p21 transcriptional activation is due to p53 activity, in cases with dramatically decreased BRCA1 expression. Our findings provide evidence, indicating that BRCA1 might affect cell cycle regulation and loss of BRCA1 function due to decreased expression leads to cell cycle arrest, through p53 and p21 genes. (C) 1998 Academic Press.