Dysregulation of MicroRNAs is Associated with Expression of a Hypermethylation Defect in Primary Basal‐like Breast Cancer

Abstract

Basal-like breast cancers frequently express a hypermethylation defect associated with DNMT hyperactivity, DNMT3b overexpression, and concurrent silencing of numerous genes. Examination of methylation-sensitive gene expression in 33 primary breast cancers showed that 10/16 (63%) basal-like tumors express the hypermethylation defect, whereas only 3/17 (17%) non-basal-like tumors express this defect. We examined the expression of microRNAs (miRs) that regulate DNMT3b (miR-26a, 26b, 29a, 29b, 29c, 148a, 148b, 203) by qPCR (normalized to RNU66) in 70 primary breast cancers (36 luminal A, 13 luminal B, 5 Her2+, 16 basal-like) and 18 normal mammoplasty tissues to determine the mechanism governing DNMT3b overexpression in the hypermethylation defect. Significantly reduced expression of 29c distinguished basal-like cancers from other subtypes. miR expression patterns revealed two groups among the basal-like breast cancers corresponding to diminished expression (n=10) and normal levels of expression (n=6). These results suggest strongly that (i) reduced expression of 29c is characteristic of basal-like breast cancers, (ii) two subgroups of basal-like breast cancers can be identified based on miR expression and methylation-sensitive gene expression, and (iii) the subgroup of basal-like breast cancers with reduced expression of multiple regulatory miRs express the hypermethylation defect.