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

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Author(s)
Kalimutho, Murugan
Sinha, Debottam
Jeffery, Jessie
Nones, Katia
Srihari, Sriganesh
Fernando, Winnie C
Duijf, Pascal HG
Vennin, Claire
Raninga, Prahlad
Nanayakkara, Devathri
Mittal, Deepak
Saunus, Jodi M
Lakhani, Sunil R
Lopez, J Alejandro
Spring, Kevin J
Timpson, Paul
Gabrielli, Brian
Waddell, Nicola
Khanna, Kum Kum
Griffith University Author(s)
Year published
2018
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Show full item recordAbstract
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 ...
View more >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.
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View more >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.
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Journal Title
EMBO Molecular Medicine
Volume
10
Issue
9
Copyright Statement
© 2018 The Authors. 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.
Subject
Biological sciences
Other biological sciences not elsewhere classified
Biomedical and clinical sciences