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 Hg Duijf; Claire Vennin; Prahlad Raninga; Devathri Nanayakkara; Deepak Mittal; Jodi M Saunus; Sunil R Lakhani; J Alejandro López; Kevin J Spring; Paul Timpson; Brian Gabrielli; Nicola Waddell; Kum Kum Khanna

doi:10.15252/emmm.201708566

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

EMBO Mol Med. 2018 Sep;10(9):e8566. doi: 10.15252/emmm.201708566.

Authors

Murugan Kalimutho^{1

2}, Debottam Sinha^{3

2}, Jessie Jeffery³, Katia Nones^{3

4}, Sriganesh Srihari⁵, Winnie C Fernando³, Pascal Hg Duijf⁶, Claire Vennin^{7

8}, Prahlad Raninga³, Devathri Nanayakkara³, Deepak Mittal³, Jodi M Saunus^{3

9}, Sunil R Lakhani^{9

10

11}, J Alejandro López^{3

2}, Kevin J Spring^{12

13

14}, Paul Timpson^{7

8}, Brian Gabrielli^{6

15}, Nicola Waddell³, Kum Kum Khanna¹

Affiliations

¹ QIMR Berghofer Medical Research Institute, Herston, Qld, Australia murugan.kalimutho@qimrberghofer.edu.au kumkum.khanna@qimrberghofer.edu.au.
² School of Natural Sciences, Griffith University, Nathan, Qld, Australia.
³ QIMR Berghofer Medical Research Institute, Herston, Qld, Australia.
⁴ Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Qld, Australia.
⁵ Computational Systems Biology Laboratory, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Qld, Australia.
⁶ University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia.
⁷ Cancer Division, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, NSW, Australia.
⁸ Faculty of Medicine, St Vincent's Clinical School, University of NSW, Sydney, NSW, Australia.
⁹ Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia.
¹⁰ School of Medicine, The University of Queensland, Herston, Qld, Australia.
¹¹ Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Qld, Australia.
¹² Liverpool Clinical School, University of Western Sydney, Liverpool, NSW, Australia.
¹³ Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia.
¹⁴ South Western Sydney Clinical School, University of New South Wales, Liverpool, NSW, Australia.
¹⁵ Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia.

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: CEP55; aneuploidy; breast cancer; centrosomal protein; genomic instability.

Publication types

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

MeSH terms

Aneuploidy*
Breast Neoplasms / pathology
CDC2 Protein Kinase / metabolism
Caspases / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Death
Cell Line, Tumor
Cyclin B / metabolism
Cytokinesis*
Gene Expression
Gene Knockdown Techniques
Humans
Mitosis*
Models, Biological
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*

Substances

Cell Cycle Proteins
Cep55 protein, human
Cyclin B
Nuclear Proteins
CDC2 Protein Kinase
CDK1 protein, human
Caspases