The ability to prevent pre-cancerous lesions from progressing to lung cancer in at risk individuals is critical for reducing mortality due to this disease. Green tea and its polyphenolic constituent (-)-epigallocatechin gallate (EGCG) are effective agents for chemoprevention of lung cancer in mice. The molecular mechanism(s) and the relative importance of green tea constituents are incompletely characterized, particularly in vivo. Inhibition of AP-1 signaling, a family of transcription factors implicated in a variety of tumorigenic processes, is one mechanism through which green tea has been proposed to act and may be a key mediator of many of the chemopreventive effects of green tea. The long-term goal of our research is to identify safe and efficacious compounds for chemoprevention of lung cancer. Understanding the molecular mechanisms used by active chemopreventive agents will aid in the selection and design of improved agents and improve our understanding of lung tumorigenesis. In the present study, we propose to use a transgenic model for conditional expression of TAM67, a dominant negative cjun mutant, to determine the role of AP-1 inhibition in the molecular mechanism of green tea in lung cancer chemoprevention. Our hypothesis is that the chemopreventive efficacy of green tea is mediated via inhibition of AP-1 and that activation of AP-1 signaling is critical for lung tumor progression.
Specific Aim 1 will determine the efficacy of the green tea extract Polyphenon E, Polyphenon E without EGCG and EGCG alone during lung cancer chemoprevention in the presence and absence of AP-1 inhibition. These experiments will determine the involvement of AP-1 in the chemopreventive activity of green tea or its components.
Specific Aim 2 will determine the effect of AP-1 inhibition on late stage lung tumor progression in a transgenic mouse model. The use of the conditional transgenic model in this aim will allow us to determine the role of AP-1 in the progression of pre-cancerous lesions in the lung to adenocarcinoma.
Lung cancer causes more deaths in the United States than any other type of cancer and preventing the progression of pre-cancerous lesions to cancer is an important component in reducing deaths due to the disease. Several agents, including green tea extracts, have successfully inhibited lung tumor formation in mice but how they work is not well understood. These experiments will determine the involvement of a specific family of molecules named activator protein 1 (AP-1) in the preventive effect of green tea, information that will be useful in designing improved compounds for preventing lung tumor formation.
| Tichelaar, Jay W; Yan, Ying; Tan, Qing et al. (2010) A dominant-negative c-jun mutant inhibits lung carcinogenesis in mice. Cancer Prev Res (Phila) 3:1148-56 |
