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Subtype-specific micro-RNA expression signatures in breast cancer progression.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Haakensen, Vilde D 
Nygaard, Vegard 
Greger, Liliana 
Aure, Miriam R 
Fromm, Bastian 

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.

Description

Keywords

DCIS, biomarker, breast cancer invasion, miRNA, subtype, Biomarkers, Tumor, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Intraductal, Noninfiltrating, Chromosome Mapping, Cluster Analysis, Disease Progression, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs, Multigene Family, Neoplasm Invasiveness, Reproducibility of Results, Transcriptome

Journal Title

Int J Cancer

Conference Name

Journal ISSN

0020-7136
1097-0215

Volume Title

139

Publisher

Wiley
Sponsorship
Cancer Research Uk (None)
European Commission FP7 Network of Excellence (NoE) (260791)
European Commission (260791)
European Commission FP7 Collaborative projects (CP) (258967)
Cancer Research UK (CB4140)
Cancer Research UK (unknown)
Cancer Research UK (C507/A16278)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Cancer Research Uk (None)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
This work was performed as part of the EurocanPlatform which has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 260791. Portions of this research (Venn diagram creator) were supported by the W.R. Wiley Environmental Molecular Science Laboratory, a national scientific user facility sponsored by the U.S. Department of Energy's Office of Biological and Environmental Research and located at PNNL. PNNL is operated by Battelle Memorial Institute for the U.S. Department of Energy under contract DE-AC05-76RL0 1830.