Mitotic chromosomal instability and cancer: mouse modelling of the human disease

Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, provides the evolutionary fuel to initiate and propagate the transformed state of multiple forms of cancer.The mitotic checkpoint is seldom lost or weakened in human tumours.Mitotic checkpoint overactivation is a more frequent observation in human tumours and is sufficient to generate CIN in vivo and in vitro. Mitotic checkpoint overactivation results in a prolonged mitosis, abnormal stabilization of cyclin B1 and securin, and an increased incidence of merotelic attachments and lagging chromosomes.Many of the key regulators of the mitotic checkpoint are downstream targets of the Rb tumour suppressor pathway and are therefore upregulated in most human tumours.The consequences of CIN are manifold and context-dependent. Although CIN can initiate tumour formation in many mouse models, under some conditions it decreases cellular fitness, providing a potential tumour suppressor effect. This effect is nevertheless often overcome, giving rise to the karyotypic complexity observed in advanced tumours.Mitotic checkpoint overactivation could prove effective as a novel therapeutic target as mitotic checkpoint loss is incompatible with cellular viability.