Long-range objective: Establish therapeutic approaches that can be used to treat preneoplastic disease. Reversal of premalignant disease is one goal of cancer prevention treatment programs. Interruption of the malignant process at an early stage is preferable to treating the fully developed, and perhaps metastatic, cancer. While inroads have been made in identifying therapeutic agents for reversal of human malignancy, investigations continue. Mechanism-based preclinical and clinical studies are utilized to identify stages of treatable premalignancy and the most appropriate genetic and cellular targets. This study will test the role of specific genetic mechanisms possibly responsible for reversal of premalignant disease utilizing a unique transgenic mouse model of cancer development. In this model temporal expression of the initiating oncoprotein (Simian Virus SV40 T Antigen (TAg)) is conditionally regulated by the tetracycline responsive gene expression (tet responsive) system and directed to epithelial cells by the mouse mammary tumor virus long terminal repeat (MMTV-LTR). When expression of the oncoprotein is terminated after four months, hyperplasia reverses. In contrast, when oncoprotein expression is terminated after seven months, no reversal of hyperplasia is found. Adenocarcinomas that can metastasize to the lung develop between nine and twelve months of age when TAg expression is not interrupted. Specific accomplishments for this proposal: 1) Establish if p53 and Bax induction are critical genetic pathways for the successful reversal of premalignant disease in the whole animal. 2) Determine why pathways that mediate reversal at an early stage of cancer progression in this model cannot promote reversal at a later stage.
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