Coordinate Dysregulation of Multiple MicroRNAs that Regulate DNMT3b Expression Characterizes A Subset of Basal‐like Breast Cancers

Abstract

Basal‐like breast cancers frequently express a hypermethylation defect associated with DNMT hyperactivity and DNMT3b overexpression. To determine the mechanism governing DNMT3b overexpression, we examined the expression of microRNAs (miRs) that regulate DNMT3b (miR‐29a, 29b, 29c, 148a, 148b) or are predicted to regulate DNMT3b (26a, 26b, 203, 222) by qPCR (normalized to RNU66) in 70 primary breast cancers (36 luminal A, 13 luminal B, 5 Her2+, 16 basal‐like) and 18 normal breast tissues. Significantly reduced expression of miR‐29c distinguished basal‐like breast cancers from other subgroups. MiR expression patterns revealed two groups among basal‐like breast cancers corresponding to low expression (n=10) and high expression (n=6). Average miR expression was significantly reduced in low vs. high groups (4.4 to 22.2‐fold difference; p<0.05). 50% of basal‐like tumors showed reduced expression of 7/9 miRs compared to 22% of luminal A, 15% of luminal B and 20% of HER2+ tumors. 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 patterns, and (iii) subgroup of basal‐like breast cancers with reduced expression of multiple regulatory miRs may correspond to those expressing a hypermethylation defect related to DNMT3b overexpression.UNC University Cancer Research Fund