title: Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo.
abstract: BACKGROUND
  Optimal expression and proper function of key mitotic proteins facilitate control and repair processes that aim to prevent loss or gain of chromosomes, a hallmark of cancer. Altered expression of small regulatory microRNAs is associated with tumourigenesis and metastasis but the impact on mitotic signalling has remained unclear.
  
  
  METHODS
  Cell-based high-throughput screen identified miR-378a-5p as a mitosis perturbing microRNA. Transient transfections, immunofluorescence, western blotting, time-lapse microscopy, FISH and reporter assays were used to characterise the mitotic anomalies by excess miR-378a-5p. Analysis of microRNA profiles in breast tumours was performed.
  
  
  RESULTS
  Overexpression of miR-378a-5p induced numerical chromosome changes in cells and abrogated taxol-induced mitotic block via premature inactivation of the spindle assembly checkpoint. Moreover, excess miR-378a-5p triggered receptor tyrosine kinase-MAP kinase pathway signalling, and was associated with suppression of Aurora B kinase. In breast cancer in vivo, we found that high miR-378a-5p levels correlate with the most aggressive, poorly differentiated forms of cancer.
  
  
  CONCLUSIONS
  Downregulation of Aurora B by excess miR-378a-5p can explain the observed microtubule drug resistance and increased chromosomal imbalance in the microRNA-overexpressing cells. The results suggest that breast tumours may deploy high miR-378a-5p levels to gain growth advantage and antagonise taxane therapy.
authors.affiliation: 1] VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland [2] Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Winsel
authors.affiliation: 1] VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland [2] Centre for Biotechnology, University of Turku, 20520 Turku, Finland [3] Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery, University of Turku, 20520 Turku, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Mäki-Jouppila
authors.affiliation: 1] VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland [2] Centre for Biotechnology, University of Turku, 20520 Turku, Finland [3] Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery, University of Turku, 20520 Turku, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Tambe
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway.
authors.forename: M R
authors.initials: MR
authors.lastname: Aure
authors.affiliation: 1] VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland [2] Turku Doctoral Programme of Molecular Medicine, University of Turku, 20520 Turku, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Pruikkonen
authors.affiliation: 1] VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland [2] Turku Graduate School of Biomedical Sciences, University of Turku, 20520 Turku, Finland.
authors.forename: A-L
authors.initials: AL
authors.lastname: Salmela
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Halonen
authors.affiliation: 1] Department of Genetics, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway [2] The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway.
authors.forename: S-K
authors.initials: SK
authors.lastname: Leivonen
authors.affiliation: VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Kallio
authors.affiliation: 1] Department of Genetics, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway [2] The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway.
authors.forename: A-L
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: 1] VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland [2] Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kallio
mesh_terms: D064107:Aurora Kinase B / Q000037:antagonists & inhibitors; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000502:physiology; D049109:Cell Proliferation; D020090:Chromosome Segregation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology*; D008938:Mitosis; D060787:Neoplasm Grading; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D002352:Carrier Proteins; C526012:MIRN378 microRNA, human; D035683:MicroRNAs; C455622:PPARGC1B protein, human; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; C576921:AURKB protein, human; D064107:Aurora Kinase B; D048049:Extracellular Signal-Regulated MAP Kinases