MicroRNAs are dysregulated in breast cancer. Heterogeneous Nuclear Ribonucleoprotein A21 (HNRNPA21) is a reader of the N(6)-methyladenosine (m6A) mark in primary-miRNAs (pri-miRNAs) and promotes DROSHA processing to precursor-miRNAs (pre-miRNAs). We examined the expression of writers， readers， and erasers of m6A and report that HNRNPA21 expression is higher in tamoxifen-resistant LCC9 breast cancer cells as compared to parental， tamoxifen-sensitive MCF-7 cells. To examine how increased expression of HNRNPA21 affects miRNA expression， HNRNPA21 was transiently overexpressed (~5.4-fold) in MCF-7 cells for whole genome miRNA profiling (miRNA-seq). 148 and 88 miRNAs were up- and down-regulated， respectivel... More
MicroRNAs are dysregulated in breast cancer. Heterogeneous Nuclear Ribonucleoprotein A21 (HNRNPA21) is a reader of the N(6)-methyladenosine (m6A) mark in primary-miRNAs (pri-miRNAs) and promotes DROSHA processing to precursor-miRNAs (pre-miRNAs). We examined the expression of writers， readers， and erasers of m6A and report that HNRNPA21 expression is higher in tamoxifen-resistant LCC9 breast cancer cells as compared to parental， tamoxifen-sensitive MCF-7 cells. To examine how increased expression of HNRNPA21 affects miRNA expression， HNRNPA21 was transiently overexpressed (~5.4-fold) in MCF-7 cells for whole genome miRNA profiling (miRNA-seq). 148 and 88 miRNAs were up- and down-regulated， respectively， 48 h after transfection and 177 and 172 up- and down-regulated， respectively， 72 h after transfection. MetaCore Enrichment analysis identified progesterone receptor action and transforming growth factor β (TGFβ) signaling via miRNA in breast cancer as pathways downstream of the upregulated miRNAs and TGFβ signaling via SMADs and Notch signaling as pathways of the downregulated miRNAs. GO biological processes for mRNA targets of HNRNPA21-regulated miRNAs included response to estradiol and cell-substrate adhesion. qPCR confirmed HNRNPA2B1 downregulation of miR-29a-3p， miR-29b-3p， and miR-222 and upregulation of miR-1266-5p， miR-1268a， miR-671-3p. Transient overexpression of HNRNPA21 reduced MCF-7 sensitivity to 4-hydroxytamoxifen and fulvestrant， suggesting a role for HNRNPA21 in endocrine-resistance.
