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 centro-acinar 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, AR and TGF-alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.