¹Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA

²Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA

³Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA

⁴Departments of Human Genetics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, NY 10021, USA

⁵Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio, OH 44195, USA

⁶Department of Oncology, University Hospital Lund, Sweden

Correspondence to: B A Arrick, Dartmouth Medical School, Kellogg Box 0128, Hanover, New Hampshire, NH 03755, USA; E-mail: Bradley.Arrick@dartmouth.edu

A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor- (ER). Previous investigation suggests that methylation of CpGs within the ER promoter mediates repression of gene expression in some ER-negative breast cancers. To determine if methylation of CpGs within the ER promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ER gene in 40 ER-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylation-sensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P<0.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ER gene in BRCA1-linked breast cancers.

Oncogene (2002) 21, 7034-7041. doi:10.1038/sj.onc.1205844

BRCA1; estrogen receptor; methylation; breast cancer