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Basal‐like breast cancers express a hypermethylation defect
Author(s) -
Risher J. Devon,
Parker Joel S.,
Rivenbark Ashley G.,
Jones Wendell D.,
Carey Lisa,
Livasy Chad A.,
Coleman William B.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.898.23
Subject(s) - dna methylation , cdh1 , biology , methylation , breast cancer , bisulfite sequencing , basal (medicine) , gene silencing , cancer research , microarray , microarray analysis techniques , epigenetics , cancer , tissue microarray , gene , pathology , gene expression , genetics , medicine , cell , endocrinology , cadherin , insulin
Breast cancer cell lines of the hypermethylator phenotype are characterized by the methylation‐dependent silencing of six genes (CEACAM6, CDH1, ESR1, SCNN1A, LCN2, CST6), and exhibit elevated DNMT activity related to overexpression of DNMT3b protein. Examination of the UNC Microarray Database reveals that 19/88 (22%) primary breast tumors lack expression of these genes. Of these putative hypermethylator tumors, 100% are of the basal‐like subtype. These putative hypermethylator tumors represent 83% (19/23) of basal‐like tumors in the dataset. Analysis of a second microarray dataset (from MD Anderson Cancer Center, n=133) identified 26/32 (81%) basal‐like tumors to be putative hypermethylators. Methylation‐specific PCR confirmed that lack of normal gene expression among basal‐like tumors was due to promoter hypermethylation: 7/10 (70%) basal‐like tumors exhibit methylation of 5–6 indicator genes and bisulfite sequencing showed extensive promoter hypermethylation. These findings strongly suggest that basal‐like breast cancers express a hypermethylation defect and that the resulting molecular signature contributes to the clinical behavior and poor prognosis associated with these neoplasms. Further, recognition of this fundamental biological property of the basal‐like breast cancers presents new molecular targets for development of novel treatment strategies. Support: NIH CA78343.