CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer.
Murugan KalimuthoDebottam SinhaJessie JefferyKatia NonesSriganesh SrihariWinnie C FernandoPascal Hg DuijfClaire VenninPrahlad RaningaDevathri NanayakkaraDeepak MittalJodi M SaunusSunil R LakhaniJ Alejandro LópezKevin J SpringPaul TimpsonBrian GabrielliNicola WaddellKum Kum KhannaPublished in: EMBO molecular medicine (2019)
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.
Keyphrases
- cell death
- cell cycle
- cell fate
- cell cycle arrest
- induced apoptosis
- transcription factor
- cell proliferation
- pi k akt
- breast cancer cells
- endothelial cells
- signaling pathway
- copy number
- endoplasmic reticulum stress
- squamous cell carcinoma
- regulatory t cells
- oxidative stress
- dendritic cells
- papillary thyroid
- gene expression
- immune response
- genome wide
- free survival