title: Individual and combined effects of DNA methylation and copy number alterations on miRNA expression in breast tumors.
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.
authors.forename: Miriam Ragle
authors.initials: MR
authors.lastname: Aure
authors.forename: Suvi-Katri
authors.initials: SK
authors.lastname: Leivonen
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleischer
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhu
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
authors.forename: Jan
authors.initials: J
authors.lastname: Alsner
authors.forename: Trine
authors.initials: T
authors.lastname: Tramm
authors.forename: Riku
authors.initials: R
authors.lastname: Louhimo
authors.forename: Grethe I Grenaker
authors.initials: GI
authors.lastname: Alnæs
authors.forename: Merja
authors.initials: M
authors.lastname: Perälä
authors.forename: Florence
authors.initials: F
authors.lastname: Busato
authors.forename: Nizar
authors.initials: N
authors.lastname: Touleimat
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Olga G
authors.initials: OG
authors.lastname: Troyanskaya
authors.forename: Ole Christian
authors.initials: OC
authors.lastname: Lingjærde
authors.forename: Kristine Kleivi
authors.initials: KK
authors.lastname: Sahlberg
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004261:DNA Replication; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs