title: Subtype-specific micro-RNA expression signatures in breast cancer progression.
abstract: Robust markers of invasiveness may help reduce the overtreatment of in situ carcinomas. Breast cancer is a heterogeneous disease and biological mechanisms for carcinogenesis vary between subtypes. Stratification by subtype is therefore necessary to identify relevant and robust signatures of invasive disease. We have identified microRNA (miRNA) alterations during breast cancer progression in two separate datasets and used stratification and external validation to strengthen the findings. We analyzed two separate datasets (METABRIC and AHUS) consisting of a total of 186 normal breast tissue samples, 18 ductal carcinoma in situ (DCIS) and 1,338 invasive breast carcinomas. Validation in a separate dataset and stratification by molecular subtypes based on immunohistochemistry, PAM50 and integrated cluster classifications were performed. We propose subtype-specific miRNA signatures of invasive carcinoma and a validated signature of DCIS. miRNAs included in the invasive signatures include downregulation of miR-139-5p in aggressive subtypes and upregulation of miR-29c-5p expression in the luminal subtypes. No miRNAs were differentially expressed in the transition from DCIS to invasive carcinomas on the whole, indicating the need for subtype stratification. A total of 27 miRNAs were included in our proposed DCIS signature. Significant alterations of expression included upregulation of miR-21-5p and the miR-200 family and downregulation of let-7 family members in DCIS samples. The signatures proposed here can form the basis for studies exploring DCIS samples with increased invasive potential and serum biomarkers for in situ and invasive breast cancer.
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|The K. G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Vilde D
authors.initials: VD
authors.lastname: Haakensen
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Vegard
authors.initials: V
authors.lastname: Nygaard
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
authors.forename: Liliana
authors.initials: L
authors.lastname: Greger
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|The K. G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Aure
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Bastian
authors.initials: B
authors.lastname: Fromm
authors.affiliation: Department of Breast and Endocrine Surgery, Akershus University Hospital, Lorenskog, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ida R K
authors.initials: IR
authors.lastname: Bukholm
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway.
authors.forename: Torben
authors.initials: T
authors.lastname: Lüders
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.|Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Git
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.|Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|The K. G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
authors.forename: Alvis
authors.initials: A
authors.lastname: Brazma
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|The K. G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|Department of Informatics, University of Oslo, Oslo, Norway.|Institute of Cancer Genetics and Informatics, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Eivind
authors.initials: E
authors.lastname: Hovig
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Åslaug
authors.initials: Å
authors.lastname: Helland
mesh_terms: D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000473:pathology; D002874:Chromosome Mapping; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D009361:Neoplasm Invasiveness; D015203:Reproducibility of Results; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs
keywords: DCIS; biomarker; breast cancer invasion; miRNA; subtype