Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells

Background & Aims: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed In pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter. Methods: Two independently generated transgenic mouse lines overexpress 50-, 43-, 28-, 26-, and :16-kilodalton AR forms in the pancreas. Results: Morphologic and immunohistochemical examinations suggest that small Intralobular duct and centroacinar cells proliferate In response to AR In these mice. AR transgenic mice display Increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression In pancreatic duct cells. In contrast to TGF-alpha transgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight Induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor In cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of Isolated acini In vitro comparable to the situation In vivo. Conclusions: These data suggest that AR Induces a mitogenic response selectively In small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AIR and TGF-alpha, display different biological effects when overexpressed In the exocrine pancreas in vivo.