Role of CDK4 in Breast Development and Cancer; Annual summary 10 Mar 2005-9 Mar 2008

摘要

Cdk4 is an important regulator of GI/S cell cycle progression in mammalian cells. In humans the Cdk4 gene is amplified in 16% of sporadic breast tumors. In mice the loss of Cdk4 affects the development of the mammary glands. Our studies to determine the role of Cdk4 in Neu Wnt-1 and Ras-induced breast tumorigenesis indicated that the absence of Cdk4 impairs Neu and Ras-induced mammary tumorigenesis but not that induced by Wnt-1. Specifically while the tumor incidences in Cdk4-null MMTV-Ras and MMTV-Neu mice were dramatically reduced when compared to their respective wild-type transgenic counterparts (0% versus 70% and 14% versus 97% respectively) the loss of Cdk4 did not affect the tumor incidence in the MMTV-Wnt-1 mouse model. In addition to Cdk4 null models we also assessed the role of the Cdk4R24C mutation played in mammary tumorigenesis. Interestingly the onset of tumors is significantly delayed in MMTV-Ras transgenic mice that express the hyperactive Cdk4R24C mutated allele when compared to those mice that express wild-type Cdk4. Analysis of the tumors and normal tissues suggests that the Cdk4 gene may play a role in modulating oncogenic stress-induced DNA damage checkpoint responses.