Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours.
We assessed expression of the BRCA1, CTCF and DNMT3b methyltransferase genes along with BRCA1 promoter methylation to better define the epigenetic events involved in BRCA1 inactivation in sporadic breast cancer. These gene expression patterns were determined in 54 sporadic breast tumours by immunohistochemistry and the methylation status of the BRCA1 promoter was evaluated using methylation-specific PCR. We observed significant DNMT3b expression in 80% of the tumours and that 43% of tumours exhibited novel cytoplasmic CTCF expression. Pairwise analyses of gene expression patterns showed that 28/32 tumours lacked BRCA1 expression and also exhibited cytoplasmic CTCF staining, while 24/32 of these tumours also overexpressed DNMT3b. Furthermore, 86% of the BRCA1 low-expressing tumours were methylated at the BRCA1 promoter and a subset of these tumours displayed both cytoplasmic CTCF and increased DNMT3b expression. Thus, tumour subsets exist that display concurrent decreased BRCA1 expression, BRCA1 promoter methylation, cytoplasmic CTCF expression and with DNMT3b over-expression. We suggest that these altered CTCF and DNMT3b expression patterns represent (a) critical events responsible for the epigenetic inactivation of BRCA1 and (b) a diagnostic signature for epigenetic inactivation of other tumour suppressor genes in sporadic breast tumours.
Butcher
Darci T
DT
The University of Western Ontario and the London Regional Cancer Program, London Health Sciences Centre, Room A4-134, 790 Commissioners Rd. East, London, Ont., Canada N6A 4L6.
Rodenhiser
David I
DI
D000368:Aged; D019313:BRCA1 Protein / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D000076246:CCCTC-Binding Factor; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism*; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019398:Genes, BRCA1; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
D019313:BRCA1 Protein; D000076246:CCCTC-Binding Factor; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D000097584:DNA Methyltransferase 3B; C000619697:CTCF protein, human