Understanding the molecular basis for the differential response of tumors to therapy is a primary goal of molecular oncology. Reduced expression of the cdk inhibitor p27/Kip1 is frequently observed in a wide range of human tumors and this correlates with poor prognosis. In this application, we propose to use autochthonous murine tumor models to examine the role of p27/Kip1 in tumor response to systemically administered chemo- and radio-therapy, p27 is a cyclin/cdk inhibitor that mediates cell cycle arrest in response to extracellular signals and cell-cell contact. Our laboratory, using mouse models, was the first to demonstrate that p27 functions as a tumor suppressor gene. One mechanism of tumor suppression by p27 is to reduce tumor cell proliferation and hence tumor growth. New data shows that p27 deficiency also results in defective cell cycle checkpoints following DNA damage, and increases the sensitivity to mutagenesis. This is the first evidence, to our knowledge, linking p27 to mutagenesis and the cellular response to DNA damage. Most cancer therapy agents are genotoxic, suggesting a link between p27 and tumor response to therapy. The objective of this application is to test the hypothesis that loss of p27 compromises the cellular response to commonly used chemo- and radio-therapeutic agents, leading to an increase in mutagenesis and genetic instability. This in turn may result in altered tumor cell sensitivity to these agents. These ideas will be tested in four stages. First, the role of p27 in regulating cdk activity and initiating the S and G2/M cell cycle checkpoints in response to DNA damage will be determined. Second, the effect of p27 reduction on mutagenesis and chromosomal instability will be measured in vivo. Third, the impact of p27 deficiency on the response of autochthonous tumors to chemo- and radiotherapy will be directly measured. Finally, the effect of restoration of p27 expression on tumor regression will be determined. These experiments will reveal the molecular and cellular basis for the poor clinical outcome associated with p27 deficient tumors. This knowledge can then be applied to improve treatment design and regimen in the clinical setting.
