MASTL overexpression promotes chromosome instability and metastasis in breast cancer.

Rogers, S; McCloy, RA; Parker, BL; Gallego-Ortega, D; Law, AMK; Chin, VT; Conway, JRW; Fey, D; Millar, EKA; O'Toole, S; Deng, N; Swarbrick, A; Chastain, PD; Cesare, AJ; Timpson, P; Caldon, CE; Croucher, DR; James, DE; Watkins, DN; Burgess, A

MASTL overexpression promotes chromosome instability and metastasis in breast cancer.

Rogers, S McCloy, RA Parker, BL Gallego-Ortega, D Law, AMK Chin, VT Conway, JRW Fey, D Millar, EKA O'Toole, S Deng, N Swarbrick, A Chastain, PD Cesare, AJ Timpson, P Caldon, CE Croucher, DR James, DE Watkins, DN Burgess, A

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Publisher:: NATURE PUBLISHING GROUP
Publication Type:: Journal Article
Citation:: Oncogene, 2018, 37, (33), pp. 4518-4533
Issue Date:: 2018-08

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Field	Value	Language
dc.contributor.author	Rogers, S
dc.contributor.author	McCloy, RA
dc.contributor.author	Parker, BL
dc.contributor.author	Gallego-Ortega, D
dc.contributor.author	Law, AMK
dc.contributor.author	Chin, VT
dc.contributor.author	Conway, JRW
dc.contributor.author	Fey, D
dc.contributor.author	Millar, EKA
dc.contributor.author	O'Toole, S
dc.contributor.author	Deng, N
dc.contributor.author	Swarbrick, A
dc.contributor.author	Chastain, PD
dc.contributor.author	Cesare, AJ
dc.contributor.author	Timpson, P
dc.contributor.author	Caldon, CE
dc.contributor.author	Croucher, DR
dc.contributor.author	James, DE
dc.contributor.author	Watkins, DN
dc.contributor.author	Burgess, A
dc.date.accessioned	2022-04-13T12:23:44Z
dc.date.available	2018-04-08
dc.date.available	2022-04-13T12:23:44Z
dc.date.issued	2018-08
dc.identifier.citation	Oncogene, 2018, 37, (33), pp. 4518-4533
dc.identifier.issn	0950-9232
dc.identifier.issn	1476-5594
dc.identifier.uri	http://hdl.handle.net/10453/156215
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	NATURE PUBLISHING GROUP
dc.relation.ispartof	Oncogene
dc.relation.isbasedon	10.1038/s41388-018-0295-z
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences, 1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Actin Cytoskeleton
dc.subject.mesh	Animals
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Cell Cycle Checkpoints
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Chromosomal Instability
dc.subject.mesh	DNA Damage
dc.subject.mesh	Epithelial-Mesenchymal Transition
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	MAP Kinase Signaling System
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Mice, SCID
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Protein Serine-Threonine Kinases
dc.subject.mesh	Proto-Oncogene Proteins c-akt
dc.subject.mesh	Signal Transduction
dc.subject.mesh	TOR Serine-Threonine Kinases
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, SCID
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	DNA Damage
dc.subject.mesh	Chromosomal Instability
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	MAP Kinase Signaling System
dc.subject.mesh	Female
dc.subject.mesh	Proto-Oncogene Proteins c-akt
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	TOR Serine-Threonine Kinases
dc.subject.mesh	Epithelial-Mesenchymal Transition
dc.subject.mesh	Actin Cytoskeleton
dc.subject.mesh	Cell Cycle Checkpoints
dc.subject.mesh	Protein Serine-Threonine Kinases
dc.title	MASTL overexpression promotes chromosome instability and metastasis in breast cancer.
dc.type	Journal Article
utslib.citation.volume	37
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.date.updated	2022-04-13T12:23:37Z
pubs.issue	33
pubs.publication-status	Published
pubs.volume	37
utslib.citation.issue	33

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/156215