Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers.
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.
Archey
William B
WB
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA.
McEachern
Kristen A
KA
Robson
Mark
M
Offit
Kenneth
K
Vaziri
Susan A J
SA
Casey
Graham
G
Borg
Ake
A
Arrick
Bradley A
BA
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
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen