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MASTL overexpression promotes chromosome instability and metastasis in breast cancer.
Oncogene. 2018 08; 37(33):4518-4533.O

Abstract

MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial-mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival.

Authors+Show Affiliations

The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. Children's Medical Research Institute, The University of Sydney, Westmead, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.NSW Health Pathology, Department of Anatomical Pathology, St George Hospital, Kogarah, Sydney, New South Wales, 2217, Australia. School of Medical Sciences, UNSW Sydney, Kensington, NSW, 2033, Australia. School of Medicine and Health Sciences, Sydney Western University, Campbelltown, NSW, 2560, Australia.Sydney Medical School, Sydney University, Fisher Road, Camperdown, NSW, 2006, Australia. Department of Tissue, Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW, 2050, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst, NSW, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst, NSW, Australia.College of Medicine at Rockford, Department of Health Sciences Education, University of Illinois, Rockford, IL, 61107, USA.Children's Medical Research Institute, The University of Sydney, Westmead, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst, NSW, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst, NSW, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst, NSW, Australia. School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.Charles Perkins Centre, School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, 2006, Australia. School of Medicine, The University of Sydney, Sydney, NSW, 2006, Australia.The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst, NSW, Australia. Department of Thoracic Medicine, St Vincent's Hospital, Darlinghurst, NSW, 2010, Australia.ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia. andrew.burgess@anzac.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29743597

Citation

Rogers, Samuel, et al. "MASTL Overexpression Promotes Chromosome Instability and Metastasis in Breast Cancer." Oncogene, vol. 37, no. 33, 2018, pp. 4518-4533.
Rogers S, McCloy RA, Parker BL, et al. MASTL overexpression promotes chromosome instability and metastasis in breast cancer. Oncogene. 2018;37(33):4518-4533.
Rogers, S., McCloy, R. A., Parker, B. L., Gallego-Ortega, D., Law, A. M. K., Chin, V. T., Conway, J. R. W., Fey, D., Millar, E. K. A., O'Toole, S., Deng, N., Swarbrick, A., Chastain, P. D., Cesare, A. J., Timpson, P., Caldon, C. E., Croucher, D. R., James, D. E., Watkins, D. N., & Burgess, A. (2018). MASTL overexpression promotes chromosome instability and metastasis in breast cancer. Oncogene, 37(33), 4518-4533. https://doi.org/10.1038/s41388-018-0295-z
Rogers S, et al. MASTL Overexpression Promotes Chromosome Instability and Metastasis in Breast Cancer. Oncogene. 2018;37(33):4518-4533. PubMed PMID: 29743597.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MASTL overexpression promotes chromosome instability and metastasis in breast cancer. AU - Rogers,Samuel, AU - McCloy,Rachael A, AU - Parker,Benjamin L, AU - Gallego-Ortega,David, AU - Law,Andrew M K, AU - Chin,Venessa T, AU - Conway,James R W, AU - Fey,Dirk, AU - Millar,Ewan K A, AU - O'Toole,Sandra, AU - Deng,Niantao, AU - Swarbrick,Alexander, AU - Chastain,Paul D, AU - Cesare,Anthony J, AU - Timpson,Paul, AU - Caldon,C Elizabeth, AU - Croucher,David R, AU - James,David E, AU - Watkins,D Neil, AU - Burgess,Andrew, Y1 - 2018/05/10/ PY - 2017/10/20/received PY - 2018/04/08/accepted PY - 2018/02/27/revised PY - 2018/5/11/pubmed PY - 2019/2/23/medline PY - 2018/5/11/entrez SP - 4518 EP - 4533 JF - Oncogene JO - Oncogene VL - 37 IS - 33 N2 - MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial-mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/29743597/MASTL_overexpression_promotes_chromosome_instability_and_metastasis_in_breast_cancer_ L2 - http://dx.doi.org/10.1038/s41388-018-0295-z DB - PRIME DP - Unbound Medicine ER -