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Dysregulation of MicroRNAs Drives the Expression of a Hypermethylation Defect in Breast Cancer
Author(s) -
Sandhu Rupninder,
Roll J Devon,
Coleman William B
Publication year - 2009
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.23.1_supplement.361.1
Subject(s) - microrna , dnmt3b , gene silencing , dna methylation , cancer research , breast cancer , biology , cell culture , cancer , gene expression , genetics , gene
A subset of breast cancers express a hypermethylation defect characterized by DNMT hyperactivity, overexpression of DNMT3b, and concurrent silencing of numerous genes. This hypermethylation defect is a feature of most basal breast cancers. Our goal was to determine the mechanism responsible for DNMT3b overexpression in model breast cancer cell lines. Several microRNAs (miRs) have been implicated in the regulation of DNMT3b. To investigate the role of miRs in DNMT3b overexpression, we analyzed miRs‐29a, 29b, 29c, 148a, and 148b in a panel of 16 breast cancer cell lines classified as hypermethylators (n=10) or low frequency methylators (n=6). 80% of hypermethylator cell lines express low levels of >3 miRs and 83% of low frequency methylator cell lines express >3 miRs at normal levels. Cell lines with high DNMT3b levels (SUM185, SUM102, SUM149) expressed all miRs at low or negligible levels, whereas cell lines with low DNMT3b levels (MDA‐MB‐415, MDA‐MB‐468, BT20, ZR‐75‐1) expressed all miRs normally. Further, miR expression patterns correlated with methylation‐sensitive gene expression among these cell lines (R=0.54, p=0.012). These findings suggest that dysregulation of miR expression drives DNMT3b overexpression in hypermethylator cell lines, and identifies DNMT3b and its regulatory miRs as targets for development of novel therapeutic strategies for treating basal breast cancers. Support: NIH CA78343