Increased mdm2 expression and immunoreactivity in human pancreatic ductal adenocarcinoma

The murine double minute-2 (MDM2) gene encodes a 90 kDa protein which binds and inactivates the protein product of the p53 tumor suppressor gene. To elucidate the potential role of MDM2 in benign and malignant hyperproliferative conditions in the pancreas, we studied MDM2 expression in cultured human pancreatic cancer cells and in pancreatic tissues from normal donors, patients with pancreatic ductal adenocarcinoma and patients with chronic pancreatitis (CP). All the tested cell lines (PANC-1, COLO-357, HPAF and T3M4) expressed a 5.5 kilobase MDM2 mRNA transcript and exhibited nuclear MDM2 immunostaining. MDM2 mRNA levels were comparable in all 18 normal and 14 CP tissues for which RNA samples were available for analysis. By comparison with the normal samples, MDM2 mRNA levels were increased 6.4-fold in 8 of 12 human pancreatic cancer samples (p < 0.0001). All 8 samples exhibited nuclear MDM2 immunostaining, which was also present in 24 of 37 additional pancreatic cancers. Mild MDM2 immunoreactivity was seen in only 1 of 20 CP samples and in none of the 18 normal samples. These findings indicate that MDM2 is overexpressed in a majority of pancreatic adenocarcinomas, but not in CP samples. This selective overexpression raises the possibility that MDM2 may contribute to pancreatic neoplastic transformation by interfering with the growth-suppressing activity of wild-type p53.