Although many mouse models of lung adenocarcinoma exist, there is no mouse lung squamous cell carcinoma model that has been validated for use in preclinical lung cancer chemoprevention studies. Since most clinical chemoprevention trials of lung cancer are performed in subjects with bronchial dysplasia, development of a lung squamous cell carcinoma mouse model becomes one of the highest priorities. We have shown that lung squamous cell carcinomas can be induced chemically in several strains of mice (Wang et al. 2004) and that green tea polyphenols exhibit a significant efficacy against the development of lung squamous cell carcinomas (preliminary data section). In this proposal, we will use a standardized green tea preparation called Polyphenon E (PE) and its major component, EGCG. The overall objective of this proposal is to determine the efficacy of green tea polyphenols in a mouse lung squamous cell carcinoma model and to determine the molecular mechanism that underlies the efficacy of green tea polyphenols in this new mouse model. We hypothesize that green tea polyphenols will prevent chemically induced lung squamous cell carcinoma development and progression in a mutant p53 mouse model, and the chemopreventive effect of green tea polyphenols is, in part, mediated by AP-1.
Three aims were proposed to test this hypothesis.
Aim 1 will evaluate the effect of green tea polyphenols on lung squamous cell carcinoma carcinogenesis in a p53 mutant transgenic mouse lung carcinoma model.
Aim 2 will determine if blockade of AP-l activity will inhibit lung squamous cell carcinoma development and determine if AP-l activity is required for the chemopreventive efficacy of green tea polyphenols.
Aim 3 will perform phenotypic profiling of green tea polyphenols'efficacy against lung squamous cell carcinoma development in inbred strains of mice. The results from this proposal will provide a solid foundation for clinical trials of green tea polyphenols as a lung cancer chemopreventive agent.
The goal of this proposal is to determine the efficacy of green tea polyphenols in a mouse lung squamous cell carcinoma model and to determine the molecular mechanism that underlies the efficacy of green tea polyphenols in this new mouse model. The results from this proposal will provide a solid foundation for clinical trials of green tea polyphenols as a lung cancer chemopreventive agent.
