Beyond the one-locus-one-miRNA paradigm: microRNA isoforms enable deeper insights into breast cancer heterogeneity

Nucleic Acids Res. 2015 Oct 30;43(19):9158-75. doi: 10.1093/nar/gkv922. Epub 2015 Sep 22.

Abstract

Here we describe our study of miRNA isoforms (isomiRs) in breast cancer (BRCA) and normal breast data sets from the Cancer Genome Atlas (TCGA) repository. We report that the full isomiR profiles, from both known and novel human-specific miRNA loci, are particularly rich in information and can distinguish tumor from normal tissue much better than the archetype miRNAs. IsomiR expression is also dependent on the patient's race, exemplified by miR-183-5p, several isomiRs of which are upregulated in triple negative BRCA in white but not black women. Additionally, we find that an isomiR's 5' endpoint and length, but not the genomic origin, are key determinants of the regulation of its expression. Overexpression of distinct miR-183-5p isomiRs in MDA-MB-231 cells followed by microarray analysis revealed that each isomiR has a distinct impact on the cellular transcriptome. Parallel integrative analysis of mRNA expression from BRCA data sets of the TCGA repository demonstrated that isomiRs can distinguish between the luminal A and luminal B subtypes and explain in more depth the molecular differences between them than the archetype molecules. In conclusion, our findings provide evidence that post-transcriptional studies of BRCA will benefit from transcending the one-locus-one-miRNA paradigm and taking into account all isoforms from each miRNA locus as well as the patient's race.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argonaute Proteins / metabolism
  • Breast / metabolism
  • Breast Neoplasms / ethnology
  • Breast Neoplasms / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Loci
  • Genetic Variation
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA Isoforms / genetics
  • RNA Isoforms / metabolism
  • RNA Precursors / metabolism
  • Transcriptome

Substances

  • Argonaute Proteins
  • MicroRNAs
  • RNA Isoforms
  • RNA Precursors