The ability to stably introduce genes into the germline of mice has greatly enhanced prospects for the generation of animal models for multistage carcinogenesis. The epidermis is an ideal tissue for the development animal models since it serves as a general model for epithelial cancers and its accessibility allows macroscopic observation of neoplastic events and easy assessment of roles played by environmental factors. Through the production of transgenic lines expressing individual genes which have been implicated in epithelial carcinogenesis, mating experiments can be designed to assess synergistic events. A novel vector has been developed and utilized to produce transgenic lines expressing v-rasHa, v-fos and TGFalpha in the epidermis, and pre-neoplastic and benign phenotypes, which are prone to regression, have been observed. Malignant conversion has been observed as a rare event, but only in old animals (more 16 months). Preliminary mating experiments between fos and ras animals produced autonomous tumors but not malignant conversion. These results indicate 1.) the requirement for additional events for malignant conversion and 2.) that this transgenic model is unique in that pre-neoplastic and pre-malignant phenotypes are stable for long periods. The stability of this model allows the assessement of interactions between relevant oncogenes, tumor suppressor genes and growth factors, and the identification of clearly defined in vivo molecular mechanisms of skin carcinogenesis. The synergisms between ras, fos and TGFalpha will be further evaluated by performing mating experiments to determine whether these genes can provide the minimum events required for malignant conversion. To determine the role of p53 tumor suppressor gene loss or mutation in malignant conversion, these transgenic lines will be mated with p53 null mice, or mice that express a mutant, gain-of- function p53 gene exclusively in the epidermis. To assess alternative mechanisms for molecular carcinogenesis, transgenic mice will be produced which express deregulated myc and a dominant-negative mutant of the type II TGF-beta receptor. Transgenic mice will be promoted with TPA to accelerate tumorigenesis and to correlate transgenic results with previous chemical carcinogenesis data. Similarly, the effect of UV irradiation, a critical environmental factor for skin carcinogenesis, will be evaluated in these transgenic models. Finally, TGF-beta1 will be introduced directly into tumors by in vivo retroviral infection to assess the roles of genes which have known oncogenic potential, but are fatal as transgenes. Although not a specific aim of this proposal, the development of transgenic mouse models for multistage carcinogenesis could serve as a useful model for assessment of novel therapeutic approaches including gene therapy.
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