CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer

Murugan Kalimutho; Debottam Sinha; Jessie Jeffery; Katia Nones; Sriganesh Srihari; Winnie C. Fernando; Pascal H. G. Duijf; Claire Vennin; Prahlad Raninga; Devathri Nanayakkara; Deepak Mittal; Jodi M. Saunus; Sunil R. Lakhani; J. Alejandro Lopez; Kevin J. Spring; Paul Timpson; Brian Gabrielli; Nicola Waddell; Kum Kum Khanna

CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer

Murugan Kalimutho, Debottam Sinha, Jessie Jeffery, Katia Nones, Sriganesh Srihari, Winnie C. Fernando, Pascal H. G. Duijf, Claire Vennin, Prahlad Raninga, Devathri Nanayakkara, Deepak Mittal, Jodi M. Saunus, Sunil R. Lakhani, J. Alejandro Lopez, Kevin J. Spring, Paul Timpson, Brian Gabrielli, Nicola Waddell, Kum Kum Khanna

Western Sydney University

Research output: Contribution to journal › Article › peer-review

61 Citations (Scopus)

Abstract

The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti"mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase"dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2"MYC axis. Blocking MEK1/2"PLK1 signaling therefore reduced outgrowth of basal"like syngeneic and human breast tumors in in vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2"PLK1 represents a potential therapeutic strategy for MYC"CEP55"dependent basal"like, triple"negative breast cancers.

Original language	English
Article number	e8566
Number of pages	22
Journal	EMBO Molecular Medicine
Volume	10
Issue number	9
Publication status	Published - Sept 2018

Bibliographical note

Publisher Copyright:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license

Open Access - Access Right Statement

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Keywords

aneuploidy
breast
cancer
centrosomes
genomics
mitosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

Kalimutho, M., Sinha, D., Jeffery, J., Nones, K., Srihari, S., Fernando, W. C., Duijf, P. H. G., Vennin, C., Raninga, P., Nanayakkara, D., Mittal, D., Saunus, J. M., Lakhani, S. R., Lopez, J. A., Spring, K. J., Timpson, P., Gabrielli, B., Waddell, N., & Khanna, K. K. (2018). CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer. EMBO Molecular Medicine, 10(9), Article e8566.

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abstract = "The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti{"}mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase{"}dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2{"}MYC axis. Blocking MEK1/2{"}PLK1 signaling therefore reduced outgrowth of basal{"}like syngeneic and human breast tumors in in vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2{"}PLK1 represents a potential therapeutic strategy for MYC{"}CEP55{"}dependent basal{"}like, triple{"}negative breast cancers.",

keywords = "aneuploidy, breast, cancer, centrosomes, genomics, mitosis",

author = "Murugan Kalimutho and Debottam Sinha and Jessie Jeffery and Katia Nones and Sriganesh Srihari and Fernando, {Winnie C.} and Duijf, {Pascal H. G.} and Claire Vennin and Prahlad Raninga and Devathri Nanayakkara and Deepak Mittal and Saunus, {Jodi M.} and Lakhani, {Sunil R.} and Lopez, {J. Alejandro} and Spring, {Kevin J.} and Paul Timpson and Brian Gabrielli and Nicola Waddell and Khanna, {Kum Kum}",

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language = "English",

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journal = "EMBO Molecular Medicine",

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AU - Kalimutho, Murugan

AU - Sinha, Debottam

AU - Jeffery, Jessie

AU - Nones, Katia

AU - Srihari, Sriganesh

AU - Fernando, Winnie C.

AU - Duijf, Pascal H. G.

AU - Vennin, Claire

AU - Raninga, Prahlad

AU - Nanayakkara, Devathri

AU - Mittal, Deepak

AU - Saunus, Jodi M.

AU - Lakhani, Sunil R.

AU - Lopez, J. Alejandro

AU - Spring, Kevin J.

AU - Timpson, Paul

AU - Gabrielli, Brian

AU - Waddell, Nicola

AU - Khanna, Kum Kum

PY - 2018/9

Y1 - 2018/9

N2 - The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti"mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase"dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2"MYC axis. Blocking MEK1/2"PLK1 signaling therefore reduced outgrowth of basal"like syngeneic and human breast tumors in in vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2"PLK1 represents a potential therapeutic strategy for MYC"CEP55"dependent basal"like, triple"negative breast cancers.

AB - The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti"mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase"dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2"MYC axis. Blocking MEK1/2"PLK1 signaling therefore reduced outgrowth of basal"like syngeneic and human breast tumors in in vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2"PLK1 represents a potential therapeutic strategy for MYC"CEP55"dependent basal"like, triple"negative breast cancers.

KW - aneuploidy

KW - breast

KW - cancer

KW - centrosomes

KW - genomics

KW - mitosis

UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:48089

M3 - Article

SN - 1757-4676

VL - 10

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 9

M1 - e8566

ER -

CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer

Abstract

Bibliographical note

Open Access - Access Right Statement

Keywords

UN SDGs

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