The Molecular Genetics Section has sought to elucidate the in vivo functions of peptide growth factors, and to assess the consequences of perturbing the normal regulation of those functions through the generation and analysis of transgenic mice. Overexpression of a transforming growth factor alpha (TGFalpha) transgene in mice induced a high incidence of hyperplastic and neoplastic lesions in the liver and mammary gland. TGFbeta interacted synergistically with c-Myc in hepatic, mammary and salivary tumorigenesis in TGFalpha/c-Myc bitransgenic mice. TGFalpha collaborated with a variety of chemical agents in carcinogenesis of the liver and skin, including genotoxic initiators and nongenotoxic promoters. Constitutive TGFalpha-induced EGFR stimulation substituted functionally for mutational activation of the c-Ha-ras gene in skin tumorigenesis. Our results show that TGFalpha can function in vivo as a potent and versatile oncogenic agent. TGFalpha overexpression also disrupted developmental processes in the stomach, pancreas, salivary and mammary glands, suggesting that TGFalpha helps regulate cellular differentiation in vivo. Mice in which transforming growth factor beta1 (TGFbeta1) expression was targeted to the pregnant mammary gland demonstrated an inhibition of lobuloalveolar development and suppression of milk production due to premature senescence of alveolar stem cells. Significantly, TGFbeta1 inhibited TGFalpha-induced mammary tumorigenesis in TGFbeta1/TGFalpha bitransgenic females. Overexpression of a hepatocyte growth factor (HGF) transgene in mice induced pleiotropic alterations in phenotype, including glomerulosclerosis and renal failure, liver enlargement associated with cellular hyperplasia and hypertrophy, disorganization and degeneration of olfactory epithelium and nerves, rectal prolapse, sporadic hind limb paralysis and a high incidence of gastrointestinal obstruction. Studies are underway to determine the mechanism(s) by which HGF induces these phenotypic changes.
