Dn. Mancini et al., CPG METHYLATION WITHIN THE 5'-REGULATORY REGION OF THE BRCA1 GENE IS TUMOR-SPECIFIC AND INCLUDES A PUTATIVE CREB BINDING-SITE, Oncogene, 16(9), 1998, pp. 1161-1169
Breast cancer is a genetic disease arising from a series of germ-line
and/or somatic DNA changes in a variety of genes, including BRCA1 and
BRCA2, DNA modifications have been shown to occur by a number of mecha
nisms that include DNA methylation, In some cases, the aberrant methyl
ation of CpGs within 5' regulatory regions has led to suppression of g
ene activity. In this report we describe a variation in the pattern of
DNA methylation within the regulatory region of the BRCA1 gene, We fo
und no evidence of methylation at CpGs within the BRCA1 promoter in a
variety of normal human tissues, However, screening of a series of ran
domly sampled breast carcinomas revealed the presence of CpG methylati
on adjacent to the BRCA1 transcription start site. One such methylated
CpG occurs at a putative CREB (cAMP-responsive element binding) trans
cription factor binding site in the BRCA1 promoter, Gelshift assays wi
th methylated and unmethylated BRCA1/CREB binding site oligonucleotide
s demonstrate that this site is sensitive to site-specific CpG methyla
tion, These data suggest that aberrant DNA methylation at regulatory s
equences in the BRCA1 locus may play a role in the transcriptional ina
ctivation of the BRCA1 gene within subclones of breast tumors, This st
udy represents the first evidence suggesting a role for DNA methylatio
n in the transcriptional inactivation of the BRCA1 in human breast can
cer.