title: Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers.
abstract: A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-alpha (ER(alpha)). Previous investigation suggests that methylation of CpGs within the ER(alpha) promoter mediates repression of gene expression in some ER(alpha)-negative breast cancers. To determine if methylation of CpGs within the ER(alpha) promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ER(alpha) gene in 40 ER(alpha)-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(alpha) gene in BRCA1-linked breast cancers.
authors.affiliation: Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Archey
authors.forename: Kristen A
authors.initials: KA
authors.lastname: McEachern
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Susan A J
authors.initials: SA
authors.lastname: Vaziri
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Arrick
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D047628:Estrogen Receptor alpha; D005260:Female; D019398:Genes, BRCA1; D008040:Genetic Linkage; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen