Abstract
Breast cancer is the cancer most often diagnosed in women. MicroRNAs (MIRs) are short RNA molecules that bind mRNA resulting in their downregulation. MIR21 has been shown to be an oncomiR in most cancer types, including breast cancer. Most of the effects of miR-21 have been attributed to hsa-miR-21-5p that is transcribed from the leading strand of MIR21, but hsa-miR-21-3p (miR-21-3p), transcribed from the lagging strand, is much less studied. The aim of the study is to analyze whether expression of miR-21-3p is prognostic for breast cancer. MiR-21-3p association with survival, clinical and pathological characteristics was analyzed in a large breast cancer cohort and validated in three separate cohorts, including TCGA and METABRIC. Analytical tools were also used to infer miR-21-3p function and to identify potential target genes and functional pathways. The results showed that in the exploration cohort, high miR-21-3p levels associated with shorter survival and lymph node positivity. In the three validation cohorts, high miR-21-3p levels associated with pathological characteristics that predict worse prognosis. Specifically, in the largest validation cohort, METABRIC (n = 1174), high miR-21-3p levels associated with large tumors, a high grade, lymph node and HER2 positivity, and shorter breast-cancer-specific survival (HR = 1.38, CI 1.13–1.68). This association remained significant after adjusting for confounding factors. The genes with expression levels that correlated with miR-21-3p were enriched in particular pathways, including the epithelial-to-mesenchymal transition and proliferation. Among the most significantly downregulated targets were MAT2A and the tumor suppressive genes STARD13 and ZNF132. The results from this study emphasize that both 3p- and 5p-arms from a MIR warrant independent study. The data show that miR-21-3p overexpression in breast tumors is a marker of worse breast cancer progression and it affects genes in pathways that drive breast cancer by down-regulating tumor suppressor genes. The results suggest miR-21-3p as a potential biomarker.
Highlights
MiRs are small non-coding RNAs that regulate gene expression by binding to 3 ́UTRs of target mRNAs to cause them to be unstable and/or degrade
Among breast tumors with amplified ERBB2, 30% were amplified for the MIR21 genomic region [31]
Examining the effect of HER2 expression on miR-21-3p associated survival showed that hazard ratios (HR) was 1.72 after adjusting for HER2 expression
Summary
MiRs are small non-coding RNAs that regulate gene expression by binding to 3 ́UTRs of target mRNAs to cause them to be unstable and/or degrade. That promoter is a site of active transcription, as it contains binding sites for transcription factors such as STAT3, AP-1, C/EBP and p53 among others [5] (reviewed in [6]). Both VMP1 and MIR21 have their own polyadenylation sites, located upstream of the miR-21 hairpin for VMP1 but downstream of the hairpin for MIR21 [2, 7]. This suggests that the two genes are transcribed independent of each other
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