The Molecular Genetics Section has sought to elucidate in vivo functions of peptide growth factors, and to determine the consequences of subverting the normal regulation of those functions through the generation and analysis of relevant transgenic models of human disease, including cancer. Overexpression of a transforming growth factor a (TGFa) transgene in mice induced a high incidence of spontaneous hyperplastic and neoplastic lesions in the mammary glands and liver. Chemical carcinogenesis and genetic experiments have demonstrated that TGFa can function in vivo as a potent and versatile oncogenic agent. Moreover, TGFa overexpression disrupted developmental processes in the stomach, pancreas, salivary and mammary glands, suggesting that TGFa also plays a role in regulating cellular differentiation in vivo. Targeting expression of a transgene encoding transforming growth factor b1 (TGFb1) to the mammary gland suppressed TGFa-induced tumorigenesis in TGFb1/TGFa bitransgenic mice, suggesting that TGFb1 should be carefully assessed as a therapeutic agent in breast cancer. Inappropriate expression of hepatocyte growth factor (HGF), also known as scatter factor, resulted in the appearance of a remarkably wide variety of tumors of both mesenchymal and epithelial origin. Typically, these tumors had elevated expression of HGF, enhanced kinase activity of its protooncoprotein receptor, c-Met, and the associated creation of autocrine signal transduction loops. Tumors included melanomas, schwannomas, rhabdomyosarcomas, liver and mammary tumors. HGF transgenic mice also demonstrated renal failure, gastrointestinal obstruction, and severe developmental abnormalities in a multitude of tissue types, including embryonic neural crest, skeletal muscle, liver, mammary glands and the olfactory mucosa. These results indicate that in vivo HGF possesses true scatter activity, and participates in both oncogenic and normal developmental processes. In addition, we have developed a novel selection assay for quantification of in vivo mutation frequencies using as a target a transgene consisting of lambda bacteriophage sequences. We are currently using this in vivo assay to determine if progression in mouse mammary cancer is associated with enhanced mutagenesis, or a mutator phenotype.
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