MicroRNA-135b regulates ERa, AR and HIF1AN and affects breast and prostate cancer cell growth

MicroRNAs (miRNAs) regulate a wide range of cellular signaling pathways and biological processes in both physiological and pathological states such as cancer. We have previously identified miR-135b as a direct regulator of androgen receptor (AR) protein level in prostate cancer (PCa). We wanted to further explore the relationship of miR-135b to hormonal receptors, particularly estrogen receptor a (ERa). Here we show that miR-135b expression is lower in ERa-positive breast tumors as compared to ERa-negative samples in two independent breast cancer (BCa) patient cohorts (101 and 1302 samples). Additionally, the miR-135b expression is higher in AR-low PCa patient samples (47 samples). We identify ERa as a novel miR-135b target by demonstrating miR-135b binding to the 3'UTR of the ERa and decreased ERa protein and mRNA level upon miR-135b overexpression in BCa cells. MiR-135b reduces proliferation of ERa-positive BCa cells MCF-7 and BT-474 as well as AR-positive PCa cells LNCaP and 22Rv1 when grown in 2D. To identify other genes regulated by miR-135b we performed gene expression studies and found a link to the hypoxia inducible factor 1a (HIF1a) pathway. We show that miR-135b influences the protein level of the inhibitor for hypoxia inducible factor 1a (HIF1AN) and is able to bind to HIF1AN 3'UTR. Our study demonstrates that miR-135b regulates ERa, AR and HIF1AN protein levels through interaction with their 3'UTR regions, and proliferation in ERa-positive BCa and AR-positive PCa cells.