CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer
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.
|Authors||Kalimutho, M.; Sinha, D.; Jeffery, J.; Nones, K.; Srihari, S.; Fernando, W. C.; Duijf, P. H.; 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.|
|Responsible Garvan Author|
|Publisher Name||EMBO Molecular Medicine|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/30108112|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14706|