Loss of normal growth control is a hallmark of
cancer progression. Therefore, understanding the early mechanisms of normal growth regulation and the changes that occur during preneoplasia may provide insights of both diagnostic and therapeutic importance. Models of dysplasia that help elucidate the mechanisms responsible for
disease progression are useful in highlighting potential targets for prevention. An important strategy in
cancer prevention treatment programs is to reduce
hyperplasia and dysplasia. This study identified abnormal upregulation of cell cycle-related
proteins cyclin D1,
cyclin-dependent kinase (CDK)4, CDK6, and phosphorylated
retinoblastoma protein (pRb) as mechanisms responsible for maintenance of
hyperplasia and dysplasia following downregulation of the initiating viral
oncoprotein Simian virus 40 (SV40)
T antigen. Significantly, p53 was not required for successful reversal of
hyperplasia and dysplasia.
Ligand-induced activation of
retinoid X receptor and PPARĪ³ agonists attenuated
cyclin D1 and CDK6 but not CDK4 or phosphorylated pRb upregulation with limited reversal of
hyperplasia and dysplasia.
PD0332991, an orally available CDK4/6 inhibitor, was able to prevent upregulation of
cyclin D1 and CDK6 as well as CDK4 and phosphorylated pRb and this correlated with a more profound reversal of
hyperplasia and dysplasia. In summary, the study distinguished CDK4 and phosphorylated pRb as targets for
chemoprevention regimens targeting reversal of
hyperplasia and dysplasia.