1. CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer
- Author
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Katia Nones, Prahlad V. Raninga, Paul Timpson, Nicola Waddell, Jessie Jeffery, Sriganesh Srihari, Sunil R. Lakhani, Winnie Fernando, Pascal H.G. Duijf, Devathri Nanayakkara, J. Alejandro Lopez, Brian Gabrielli, Debottam Sinha, Jodi M. Saunus, Claire Vennin, Kevin J. Spring, Murugan Kalimutho, Deepak Mittal, Kum Kum Khanna, 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, López, J Alejandro, Spring, Kevin J, Timpson, Paul, Gabrielli, Brian, Waddell, Nicola, and Khanna, Kum Kum
- Subjects
0301 basic medicine ,Genome instability ,Medicine (General) ,centrosomal protein ,Cyclin B ,Gene Expression ,Mitosis ,Breast Neoplasms ,Cell Cycle Proteins ,QH426-470 ,Biology ,Cell fate determination ,Models, Biological ,03 medical and health sciences ,R5-920 ,Breast cancer ,breast cancer ,Cell Line, Tumor ,CDC2 Protein Kinase ,Genetics ,medicine ,Humans ,aneuploidy ,Pharmacology & Drug Discovery ,CEP55 ,Research Articles ,Cytokinesis ,Cancer ,Cyclin-dependent kinase 1 ,Cell Death ,Nuclear Proteins ,medicine.disease ,Aneuploidy ,genomic instability ,3. Good health ,030104 developmental biology ,Medicine, Research & Experimental ,Caspases ,Gene Knockdown Techniques ,Cancer research ,biology.protein ,Molecular Medicine ,Research Article - 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 invi v 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. Refereed/Peer-reviewed
- Published
- 2018