Introduction: CEP55, discovered first by our laboratory, is a key regulator of cytokinesis, with perturbation of its levels causing cytokinesis failure and multi-nucleation. Since its discovery, CEP55 over-expression has been linked to increased aggressiveness of multiple tumor types. This overexpression has been associated with increased AKT activation, caused by the interaction of CEP55 with p110 and promoting stability of the catalytic subunit of PI3KCA. Further, it has been shown that wild-type p53 suppresses CEP55 expression by negatively regulating PLK1 creating a p53-PLK1-CEP55 axis to directly modulate CEP55 stability and cytokinesis completion. In addition, CEP55 has been shown to be part of the CIN70 gene signature that predicts chromosomal instability and poor prognosis of several tumors. However, despite these studies, it is currently unknown whether elevated Cep55 levels alone are sufficient to promote de novo tumorigenesis.
M&M: We have generated the first novel transgenic mouse model with overexpression of Cep55 from the ubiquitously expressed Rosa26 locus.
Results: We observed that Cep55 over-expression in vivo leads to a wide-spectrum of spontaneous tumor formation with a long latency period. In addition, we have generated a bi-transgenic mouse model (Cep55Tg/Tg Trp53+/-) to determine the contribution of p53 loss to Cep55-induced tumorigenesis. Interestingly, we observed a similar latency between Cep55Tg/Tg and Cep55Tg/Tg; Trp53+/- mice. However, we detected a higher incidence of tumors in Cep55Tg/Tg ; Trp53+/- compared to Cep55wt/Tg; Trp53+/- and Cep55wt/wt; Trp53+/- mice with the tumors being significantly larger and more penetrant, proliferative and metastatic in nature. In addition, we demonstrated that Cep55 overexpression induces chromosomal instability and whole genome doubling. Further, we observed that Cep55 overexpression is associated with chromosomal segregation errors in vitro. We also observed an association of Cep55 with polyploidy in a dose-dependent manner and demonstrated that Cep55 overexpression protects a polyploid subpopulation upon perturbed mitosis.
Conclusion: Collectively, our data proves the oncogenic potential of Cep55 overexpression in vivo and as an important stimulus in the initiation and progression of multiple cancer types.