Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ER alpha), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ER beta) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ER beta is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ER beta-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ER beta, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ER beta+and 32 ER beta- primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ER beta+ compared to ER beta- tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ER beta+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ER beta in TNBC cells.