title: Long non-coding RNAs differentially expressed between normal versus primary breast tumor tissues disclose converse changes to breast cancer-related protein-coding genes.
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.
authors.affiliation: Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany, and Department for Computer Science, University of Leipzig, Leipzig, Germany; RNomics Group, Department Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology - IZI, Leipzig, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Reiche
authors.affiliation: RNomics Group, Department Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology - IZI, Leipzig, Germany; LIFE Interdisciplinary Research Cluster, University of Leipzig, Leipzig, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kasack
authors.affiliation: Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany, and Department for Computer Science, University of Leipzig, Leipzig, Germany; RNomics Group, Department Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology - IZI, Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Torben
authors.initials: T
authors.lastname: Lüders
authors.affiliation: K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Eldri U
authors.initials: EU
authors.lastname: Due
authors.affiliation: K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Oncology, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Naume
authors.affiliation: Department of Breast and Endocrine Surgery, Oslo University Hospital, Ullevål, Norway.
authors.forename: Margit
authors.initials: M
authors.lastname: Riis
authors.affiliation: Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: RNomics Group, Department Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology - IZI, Leipzig, Germany; Institute for Clinical Immunology, University of Leipzig, Leipzig, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Horn
authors.affiliation: K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany, and Department for Computer Science, University of Leipzig, Leipzig, Germany; RNomics Group, Department Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology - IZI, Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hackermüller
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Department of Pediatric Research, Women and Children's Division, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Lars O
authors.initials: LO
authors.lastname: Baumbusch
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D002843:Chromatin / Q000378:metabolism; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding