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Individual and combined effects of DNA methylation and copy number alterations on miRNA expression in breast tumors

Miriam Ragle Aure12, Suvi-Katri Leivonen12, Thomas Fleischer12, Qian Zhu3, Jens Overgaard4, Jan Alsner4, Trine Tramm4, Riku Louhimo5, Grethe I Grenaker Alnæs12, Merja Perälä6, Florence Busato7, Nizar Touleimat7, Jörg Tost7, Anne-Lise Børresen-Dale12, Sampsa Hautaniemi5, Olga G Troyanskaya38, Ole Christian Lingjærde1029, Kristine Kleivi Sahlberg1112 and Vessela N Kristensen1122*

Author Affiliations

1 Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radiumhospital, 0310 Oslo, Norway

2 The KG Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway

3 Department of Computer Science, Princeton University, Princeton, NJ 08540 USA

4 Department of Experimental Clinical Oncology, Aarhus University Hospital, 8000 Aarhus, Denmark

5 Systems Biology Laboratory, Institute of Biomedicine and Genome-Scale Biology Research Program, University of Helsinki, 00014 Helsinki, Finland

6 Medical Biotechnology, VTT Technical Research Centre of Finland, 20521 Turku, Finland

7 Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA - Institut de Génomique, 91000 Evry, France

8 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544 USA

9 Biomedical Informatics Research Group, Department of Informatics, University of Oslo, 0316 Oslo, Norway

10 Centre for Cancer Biomedicine, University of Oslo, 0424 Oslo, Norway

11 Department of Research, Vestre Viken Hospital Trust, 3004 Drammen, Norway

12 Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Division of Medicine, Akershus University Hospital, 1478 Akershus, Norway

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Genome Biology 2013, 14:R126  doi:10.1186/gb-2013-14-11-r126

Published: 20 November 2013

Abstract

Background

The global effect of copy number and epigenetic alterations on miRNA expression in cancer is poorly understood. In the present study, we integrate genome-wide DNA methylation, copy number and miRNA expression and identify genetic mechanisms underlying miRNA dysregulation in breast cancer.

Results

We identify 70 miRNAs whose expression was associated with alterations in copy number or methylation, or both. Among these, five miRNA families are represented. Interestingly, the members of these families are encoded on different chromosomes and are complementarily altered by gain or hypomethylation across the patients. In an independent breast cancer cohort of 123 patients, 41 of the 70 miRNAs were confirmed with respect to aberration pattern and association to expression. In vitro functional experiments were performed in breast cancer cell lines with miRNA mimics to evaluate the phenotype of the replicated miRNAs. let-7e-3p, which in tumors is found associated with hypermethylation, is shown to induce apoptosis and reduce cell viability, and low let-7e-3p expression is associated with poorer prognosis. The overexpression of three other miRNAs associated with copy number gain, miR-21-3p, miR-148b-3p and miR-151a-5p, increases proliferation of breast cancer cell lines. In addition, miR-151a-5p enhances the levels of phosphorylated AKT protein.

Conclusions

Our data provide novel evidence of the mechanisms behind miRNA dysregulation in breast cancer. The study contributes to the understanding of how methylation and copy number alterations influence miRNA expression, emphasizing miRNA functionality through redundant encoding, and suggests novel miRNAs important in breast cancer.