The advent of transgenic technology, whereby foreign DNA is stably introduced into the mammalian germ line, has provided a powerful means to study fundamental biological questions. We are continuing to use this technology to investigate the role of growth factors, receptors and oncogenes in the initiation and development of neoplasia, and to establish useful animal models to study the pathogenesis of human disease. Both transforming growth factor alpha (TGFalpha) and epidermal growth factor (EGF) stimulate cellular proliferation by binding and activating the EGF receptor tyrosine kinase. Perturbation of the EGF receptor signal transduction pathway can transform cells in culture, and has been implicated in the development of human cancer. To test this hypothesis in vivo, transgenic mice were made bearing the human TGFalpha gene. TGFalpha overexpression was found to induce hepatocellular carcinoma, mammary adenocarcinoma, pancreatic metaplasia and fibrosis, and a hypertrophic gastropathy resembling Menetrier's disease. Detailed molecular analysis of transgenic liver neoplasia has shown that TGFalpha promotes tumor formation and plays a role in tumor progression. Furthermore, other factors that may collaborate in TGFalpha-induced hepatocarcinogenesis have been found to include expression of c-myc, insulin-like growth factor II, sex hormones, and the genetic background upon which the transgene operates. We have begun to generate transgenic mice containing foreign DNA encoding other interesting growth and differentiation factors. Transgenic mice made using an activated form of an EGF-related gene, int-3, which contains EGF repeats and is a member of the Notch gene family, develop severe hyperplastic lesions of multiple secretory glands and neoplasia of the salivary and mammary glands. The latter were also arrested in development and lactation deficient in all female int-3 transgenic mice. In addition, male mice were sterile due to epididymal hyperplasia. These findings demonstrate in vivo that expression of the activated Notch-related int-3 gene causes deregulation of normal developmental controls and hyperproliferation of glandular epithelia.
