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| Article |
| CpG methylation within the 5' regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site |
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| Debora N Mancini1,7,8, David I Rodenhiser1,7,8,a, Peter J Ainsworth1,3,5,7, Frances P O'Malley1,5,6, Shiva M Singh1,7,8, Weirong Xing2,3 and Trevor K Archer2,3,4,5 |
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1Southwestern Ontario Medical Genetics Program, London Health Sciences Centre at the University of Western Ontario, London, Ontario, Canada
2London Regional Cancer Centre at the University of Western Ontario, London, Ontario, Canada
3Department of Biochemistry at the University of Western Ontario, London, Ontario, Canada
4Department of Obstetrics and Gynecology at the University of Western Ontario, London, Ontario, Canada
5Department of Oncology at the University of Western Ontario, London, Ontario, Canada
6Department of Pathology at the University of Western Ontario, London, Ontario, Canada
7Department of Paediatrics at the University of Western Ontario, London, Ontario, Canada
8Department of Zoology at the University of Western Ontario, London, Ontario, Canada
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aAuthor for correspondence: Molecular Medical Genetics, A4WT, CHRI, London Health Sciences Centre, 800 Commissioner's Road East, London, Ontario, Canada N6C 2V5 |
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| Abstract |
| 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. |
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| Keywords |
| BRCA1; methylation; CpG dinucleotides; CREB |
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| Received 22 July 1997; revised 6 October 1997; accepted 7 October 1997 |
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| 5 March 1998, Volume 16, Number 9, Pages 1161-1169 |
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