Abstract
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 (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERβ) 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. ERβ 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 ERβ-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERβ, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERβ+and 32 ERβ− primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERβ+ compared to ERβ− tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERβ+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERβ in TNBC cells.
Highlights
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, responsible for 25% of breast cancer-related deaths [1]
RNA profiling of the MDA-MB-468, HCC1806, and Hs 578T cell lines, which belong to the basal-like 1, basal-like 2, and claudin-low TNBC subtypes, respectively
The analysis of small noncoding RNAs (sncRNAs) distribution between different subclasses revealed that in all three TNBC cell subtypes, the highest number of small RNA molecules was represented by miRNAs, followed by transfer RNA (tRNA), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs), and PIWI-interacting RNA (piRNA) (Figure 1A)
Summary
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, responsible for 25% of breast cancer-related deaths [1]. Estrogen signaling plays a key role in BC carcinogenesis and it is mediated by two receptors belonging to the nuclear receptor superfamily: ERα and ERβ, encoded by the ESR1 and ESR2 genes, respectively [6,7], that play opposite roles in hormone-responsive breast cancer progression. Both in vivo and in vitro studies demonstrated that ERα expression increases cellular proliferation and positively controls epithelial–mesenchymal transition (EMT) whereas ERβ exerts anti-proliferative effects and inhibits EMT [8]. Another factor hindering ERβ research is the poor specificity of antibodies raised against this protein, especially the ones that recognize the
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