CpG methylation within the 5' regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site.
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 mechanisms that include DNA methylation. In some cases, the aberrant methylation of CpGs within 5' regulatory regions has led to suppression of gene activity. In this report we describe a variation in the pattern of DNA methylation within the regulatory region of the BRCA1 gene. We found no evidence of methylation at CpGs within the BRCA1 promoter in a variety of normal human tissues. However, screening of a series of randomly sampled breast carcinomas revealed the presence of CpG methylation adjacent to the BRCA1 transcription start site. One such methylated CpG occurs at a putative CREB (cAMP-responsive element binding) transcription factor binding site in the BRCA1 promoter. Gelshift assays with methylated and unmethylated BRCA1/CREB binding site oligonucleotides demonstrate that this site is sensitive to site-specific CpG methylation. These data suggest that aberrant DNA methylation at regulatory sequences in the BRCA1 locus may play a role in the transcriptional inactivation of the BRCA1 gene within subclones of breast tumors. This study represents the first evidence suggesting a role for DNA methylation in the transcriptional inactivation of the BRCA1 in human breast cancer.
Mancini
D N
DN
London Health Sciences Centre, Department of Paediatrics at the University of Western Ontario, Canada.
Rodenhiser
D I
DI
Ainsworth
P J
PJ
O'Malley
F P
FP
Singh
S M
SM
Xing
W
W
Archer
T K
TK
D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019175:DNA Methylation; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D005091:Exons; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D008957:Models, Genetic; D009838:Oligodeoxyribonucleotides; D010051:Ovarian Neoplasms / Q000235:genetics; D011401:Promoter Regions, Genetic; D012016:Reference Values; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D015226:Dinucleoside Phosphates; D009838:Oligodeoxyribonucleotides; C015772:CpG dinucleotide