Long non-coding RNAs differentially expressed between normal versus primary breast tumor tissues disclose converse changes to breast cancer-related protein-coding genes

PLoS One. 2014 Sep 29;9(9):e106076. doi: 10.1371/journal.pone.0106076. eCollection 2014.

Abstract

Breast cancer, the second leading cause of cancer death in women, is a highly heterogeneous disease, characterized by distinct genomic and transcriptomic profiles. Transcriptome analyses prevalently assessed protein-coding genes; however, the majority of the mammalian genome is expressed in numerous non-coding transcripts. Emerging evidence supports that many of these non-coding RNAs are specifically expressed during development, tumorigenesis, and metastasis. The focus of this study was to investigate the expression features and molecular characteristics of long non-coding RNAs (lncRNAs) in breast cancer. We investigated 26 breast tumor and 5 normal tissue samples utilizing a custom expression microarray enclosing probes for mRNAs as well as novel and previously identified lncRNAs. We identified more than 19,000 unique regions significantly differentially expressed between normal versus breast tumor tissue, half of these regions were non-coding without any evidence for functional open reading frames or sequence similarity to known proteins. The identified non-coding regions were primarily located in introns (53%) or in the intergenic space (33%), frequently orientated in antisense-direction of protein-coding genes (14%), and commonly distributed at promoter-, transcription factor binding-, or enhancer-sites. Analyzing the most diverse mRNA breast cancer subtypes Basal-like versus Luminal A and B resulted in 3,025 significantly differentially expressed unique loci, including 682 (23%) for non-coding transcripts. A notable number of differentially expressed protein-coding genes displayed non-synonymous expression changes compared to their nearest differentially expressed lncRNA, including an antisense lncRNA strongly anticorrelated to the mRNA coding for histone deacetylase 3 (HDAC3), which was investigated in more detail. Previously identified chromatin-associated lncRNAs (CARs) were predominantly downregulated in breast tumor samples, including CARs located in the protein-coding genes for CALD1, FTX, and HNRNPH1. In conclusion, a number of differentially expressed lncRNAs have been identified with relation to cancer-related protein-coding genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Chromatin / metabolism
  • Female
  • Humans
  • Neoplasm Proteins / genetics*
  • RNA, Long Noncoding / genetics*
  • Transcription, Genetic

Substances

  • Chromatin
  • Neoplasm Proteins
  • RNA, Long Noncoding

Grants and funding

The work was supported by an extra allowance of the Medical Faculty of the University of Oslo, Norway to A-LB-D and LOB. The work was further supported by a personal mobility grant for the research exchange between Norway and Germany of the Norwegian Research Council (NFR) and the German Academic Exchange Service (DAAD) to KR, KK, JH, and LOB (Grant numbers: NFR 207835 and DAAD 50980950). This work was supported in part by the Initiative and Networking Fund of the Helmholtz Association (VH-NG738), by the Bundesministerium fur Bildung und Forschung (BMBF) through grants by the Interdisciplinary Center for Clinical Research (IZKF) at the University of Leipzig, and by the Deutsche Forschungsgemeinschaft (DFG) through the Sonderforschungsbereich 610, subproject C2 to FH. KK was supported by a formel.1 junior research grant and by LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by means of the Free State of Saxony within the framework of 42 the excellence initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.