Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo

S. Winsel, Jenni Mäki-Jouppila, Mahesh Tambe, M.R. Aure, Sofia-Maria Pruikkonen, Anna Salmela, T. Halonen, Suvi Leivonen, Lila Kallio, A.-L. Børresen-Dale, M.J. Kallio (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

11 Citations (Scopus)

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. Interpretation: 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.
Original languageEnglish
Pages (from-to)2142-2151
JournalBritish Journal of Cancer
Volume111
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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MicroRNAs
Breast Neoplasms
Aurora Kinase B
Chromosomes
M Phase Cell Cycle Checkpoints
Receptor Protein-Tyrosine Kinases
Paclitaxel
Mitosis
Drug Resistance
Microtubules
Fluorescent Antibody Technique
Transfection
Microscopy
Neoplasms
Down-Regulation
Western Blotting
Neoplasm Metastasis
Growth
Proteins
Therapeutics

Cite this

Winsel, S., Mäki-Jouppila, J., Tambe, M., Aure, M. R., Pruikkonen, S-M., Salmela, A., ... Kallio, M. J. (2014). Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo. British Journal of Cancer, 111, 2142-2151. https://doi.org/10.1038/bjc.2014.524
Winsel, S. ; Mäki-Jouppila, Jenni ; Tambe, Mahesh ; Aure, M.R. ; Pruikkonen, Sofia-Maria ; Salmela, Anna ; Halonen, T. ; Leivonen, Suvi ; Kallio, Lila ; Børresen-Dale, A.-L. ; Kallio, M.J. / Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo. In: British Journal of Cancer. 2014 ; Vol. 111. pp. 2142-2151.
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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. Interpretation: 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.",
author = "S. Winsel and Jenni M{\"a}ki-Jouppila and Mahesh Tambe and M.R. Aure and Sofia-Maria Pruikkonen and Anna Salmela and T. Halonen and Suvi Leivonen and Lila Kallio and A.-L. B{\o}rresen-Dale and M.J. Kallio",
year = "2014",
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pages = "2142--2151",
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Winsel, S, Mäki-Jouppila, J, Tambe, M, Aure, MR, Pruikkonen, S-M, Salmela, A, Halonen, T, Leivonen, S, Kallio, L, Børresen-Dale, A-L & Kallio, MJ 2014, 'Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo', British Journal of Cancer, vol. 111, pp. 2142-2151. https://doi.org/10.1038/bjc.2014.524

Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo. / Winsel, S.; Mäki-Jouppila, Jenni; Tambe, Mahesh; Aure, M.R.; Pruikkonen, Sofia-Maria; Salmela, Anna; Halonen, T.; Leivonen, Suvi; Kallio, Lila; Børresen-Dale, A.-L.; Kallio, M.J. (Corresponding Author).

In: British Journal of Cancer, Vol. 111, 2014, p. 2142-2151.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo

AU - Winsel, S.

AU - Mäki-Jouppila, Jenni

AU - Tambe, Mahesh

AU - Aure, M.R.

AU - Pruikkonen, Sofia-Maria

AU - Salmela, Anna

AU - Halonen, T.

AU - Leivonen, Suvi

AU - Kallio, Lila

AU - Børresen-Dale, A.-L.

AU - Kallio, M.J.

PY - 2014

Y1 - 2014

N2 - 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. Interpretation: 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.

AB - 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. Interpretation: 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.

U2 - 10.1038/bjc.2014.524

DO - 10.1038/bjc.2014.524

M3 - Article

VL - 111

SP - 2142

EP - 2151

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -