Mad2 upregulation mediates the chromosome instability imparted by Rb pathway inhibition

Inactivation of the Retinoblastoma (Rb) pathway is a key event in the development of chromosome instability and cancer yet the mechanisms by which this instability arises are unclear. Mad2 is an essential component of the mitotic checkpoint whose levels are frequently upregulated in solid tumors. Moreover, Mad2 overexpression is sufficient to initiate aneuploid tumor formation. Rb pathway inhibition leads to Mad2 overexpression via E2F activation but whether Mad2 is required to mediate the phenotypes of Rb pathway inhibition is unknown. Here I present work showing that chromosome instability present in cells lacking the Rb/pIO7/pI3O family of tumor suppressor genes is dependent upon Mad2 upregulation. In a mammary tumor model driven by Rb pathway inhibition, Mad2 upregulation is required for the acquisition of aneuploidy and the development of advanced anaplastic disease. Related work has shown that Mad2 is also upregulated in response to P53 loss as a result of reduced p21-mediated inhibition of Cdk activity and this upregulation is required for the CIN present in a p53 mutant tumor model. Hence, Mad2 is an essential mediator of the chromosome instability and tumor phenotypes observed upon inactivation of the two major tumor suppressor pathways involved in human oncogenesis.