TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas

Abstract To define the role of TGFα in normal tissue function and in pathogenesis, transgenic mice have been generated bearing a fusion gene consisting of the mouse metallothionein 1 promoter and a human TGFα cDNA. In these mice, human TGFα RNA and protein are abundant in many tissues and TGFα is detectable in blood and urine. The effects of TGFα overproduction in transgenic mice are pleiotropic and tissue specific. The liver frequently contains multifocal, well-differentiated hepatocellular carcinomas that express enhanced levels of human TGFα RNA. The mammary gland exhibits impeded morphogenetic penetration of epithelial duct cells into the stromal fat pad. The pancreas shows progressive interstitial fibrosis and a florid acinoductular metaplasia, during which acinar cells appear to degranulate, dedifferentiate, and assume characteristics of intercalated or centroacinar duct cells. TGFα therefore plays an important role in cellular proliferation, organogenesis, and neoplastic transformation.