Transgenic technology, in which foreign DNA is stably introduced into the mammalian gene line, represents a method to address basic biological questions that is both powerful and versatile. We are using this exciting technology to examine the role of growth factors, receptors and oncogenes in tumorigenesis, and to establish useful and novel animal models to aid in the study of pathogenesis in human disease. Transforming growth factor alpha (TGF alpha) stimulates cellular proliferation by binding to the epidermal growth factor (EGF) receptor and activating its tyrosine kinase. Perturbation of this signal transduction pathway can transform cells in culture, and has been implicated in human oncogenesis. To test this hypothesis in vivo, mice were made harboring a human TGFalpha transgene. Overexpression of TGFalpha was found to induce hepatocellular carcinoma, mammary adenocarcinoma, pancreatic metaplasia and fibrosis, and a hypertrophic gastropathy resembling Menetrier's disease. Detailed molecular analysis of lesions in these mice has confirmed that TGFalpha promotes tumor formation and plays a role in tumor progression. Analysis of double transgenic mice demonstrated that TGFalpha and the c-myc nuclear protooncogene act in a synergistic fashion in hepatocarcinogenesis. Furthermore, TGFalpha was able to collaborate with diverse chemical agents in the development of liver tumors, including genotoxic initiators and nongenotoxic promoters. We have generated mice bearing transgenes encoding other relevant growth and differentiation factors. Transgenic mice made with an activated form of an EGF-related gene, int-3, which contains numerous EGF repeat- sequences and is a member of the Notch gene family, develop severe hyperplastic and developmental lesions of multiple secretory glands and cancer of the salivary and mammary glands. These findings demonstrate in vivo that expression of the activated int-3 gene causes deregulation of normal developmental controls and hyperproliferation of glandular epithelia. In another study, mice overexpressing a transforming growth factor beta1 (TGFbeta1) transgene in the pregnant mammary gland were unable to lactate due to the inhibition of the formation of lobuloalveolar structures and suppression of endogenous milk production. These results strongly suggest that TGFbeta1 plays an important role in regulating the development and function of the mammary gland.
