CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer
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 surv...
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708566 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Murugan Kalimutho |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-81a0772c1ea5410bbe8b8145afcfbc3d |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-81a0772c1ea5410bbe8b8145afcfbc3d2025-08-20T03:46:13ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-08-0110912210.15252/emmm.201708566CEP55 is a determinant of cell fate during perturbed mitosis in breast cancerMurugan Kalimutho0Debottam Sinha1Jessie Jeffery2Katia Nones3Sriganesh Srihari4Winnie C Fernando5Pascal HG Duijf6Claire Vennin7Prahlad Raninga8Devathri Nanayakkara9Deepak Mittal10Jodi M Saunus11Sunil R Lakhani12J Alejandro López13Kevin J Spring14Paul Timpson15Brian Gabrielli16Nicola Waddell17Kum Kum Khanna18QIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteComputational Systems Biology Laboratory, Institute for Molecular Bioscience, The University of QueenslandQIMR Berghofer Medical Research InstituteUniversity of Queensland Diamantina Institute, Translational Research Institute, The University of QueenslandCancer Division, Garvan Institute of Medical Research and The Kinghorn Cancer CentreQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteCentre for Clinical Research, The University of QueenslandQIMR Berghofer Medical Research InstituteLiverpool Clinical School, University of Western SydneyCancer Division, Garvan Institute of Medical Research and The Kinghorn Cancer CentreUniversity of Queensland Diamantina Institute, Translational Research Institute, The University of QueenslandQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteAbstract 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.https://doi.org/10.15252/emmm.201708566aneuploidybreast cancercentrosomal proteinCEP55genomic instability |
| spellingShingle | 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 CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer EMBO Molecular Medicine aneuploidy breast cancer centrosomal protein CEP55 genomic instability |
| title | CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer |
| title_full | CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer |
| title_fullStr | CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer |
| title_full_unstemmed | CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer |
| title_short | CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer |
| title_sort | cep55 is a determinant of cell fate during perturbed mitosis in breast cancer |
| topic | aneuploidy breast cancer centrosomal protein CEP55 genomic instability |
| url | https://doi.org/10.15252/emmm.201708566 |
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