Glucocorticoid receptor overexpression slightly shifts microRNA expression patterns in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with limited options for clinical intervention. As with many solid tumors, TNBC is known to promote invasiveness and metastasis by secreting extracellular vesicles (EVs) capable of modulating the behaviour of recipient cells. Recent investigations have demonstrated that high expression levels of glucocorticoid receptor (GR) in TNBC are linked to therapy resistance, higher recurrence rates and increased mortality. In addition to activating protein-coding genes, GR is also involved in the expression of short non-coding RNAs including microRNAs (miRNAs or miRs). The molecular mechanisms responsible for the oncogenic effects of GR on TNBC have yet to be fully elucidated; however, emerging evidence suggests that miRNAs may play a pivotal role in tumorigenesis and metastasis. Thus, the aim of this study was to identify GR-regulated cellular and vesicular miRNAs that might contribute to the particularly oncogenic phenotype of TNBC with a high GR expression. We analyzed miRNA profiles of three TNBC cell lines using an in vitro model of GR overexpression. Next-generation sequencing revealed minor, cell line-specific changes in cellular miRNA expression, whereas vesicular miRNAs were not significantly regulated by GR. Additionally, the analysis of predicted miRNA targets failed to establish a causal link between GR-induced miRNA expression and oncogenic signaling. On the whole, given that GR influences miRNA profiles to only a small degree, other mechanisms are more likely to be responsible for the increased mortality of patients with TNBC with a high GR expression.

Prediction of clusters of miRNA binding sites in mRNA candidate genes of breast cancer subtypes

“…Dysregulation of gene expression by miRNAs is one of the causes of oncogenesis (Adhami et al, 2018), and studies about the participation of miRNAs in oncogenesis testifies to their important role in this process (Persson et al, 2011). Many studies have been devoted to the role of miRNA in various diseases, including triple-negative BC (Bar et al, 2017; Buschmann et al, 2018; Yao et al, 2018), luminal A and B subtypes of BC (Aure et al, 2017; Hannafon et al, 2016; Wang & Luo, 2015) and the HER2 subtype of BC (Halvorsen et al, 2017; Patel et al, 2016; Wang & Lin, 2013). However, there have been few reliably established associations between miRNA and target genes.…”

RNAcentral: a hub of information for non-coding RNA sequences

“…In several studies RNAcentral sequences from an organism or RNA type of interest are downloaded and then the novel ncRNAs are compared against the RNAcentral sequences to classify them or to determine if the ncRNAs have been observed before. For example, RNAcentral data were used to study miRNA expression in breast cancer (31), to annotate the sea anemone genome with ncRNAs and study miRNA-mediated modulation of the host transcriptome in cnidarian-dinoflagellate symbiosis (32), and to understand the physiological regulation of reproduction in goats (33). Additionally, Ensembl regularly imports identifiers and descriptions from RNAcentral.…”

GR silencing impedes the progression of castration-resistant prostate cancer through the JAG1/NOTCH2 pathway via up-regulation of microRNA-143-3p

“…Accumulating evidence has noted that glucocorticoid-activated GR can lead to failure of chemotherapy and tumor progression [26]. Moreover, the biology of GR represents a particularly complexity, including ligand-dependent receptor activation and subtype-specific transcription activities, and GR has been reported to modulate not only protein-encoded genes, but also activate non-coding RNA, including miRNA [27]. Previous data have revealed that GR activation stimulates cell proliferation in bladder cancer [28].…”