Esophagogastric adenocarcinoma in an E1A/E1B transgenic model involves p53disruption

We studied tumorigenesis and p53 immunostaining in a murine transgenic mode l introducing E1A/E1B under the control of the mouse mammary tumor virus-lo ng terminal repeat (MMTV-LTR) promoter in which adenocarcinoma occurs at th e squamocolumnar junction in the foregut, predominantly in males, and at no other site. Mutations of p53 are frequent in human esophageal adenocarcino ma and the E1B gene product interferes with p53-mediated apoptosis, inhibit ing turner suppression at the G(1)/S checkpoint. Transgenic animals were ge nerated utilizing a purified linear 6.7 kb fragment of plasmid DNA containi ng MMTV-LTR/E1A/E1B and were confirmed by dot blot hybridization of tail DN A to P-32-labeled E1A/E1B probe and polymerase chain reaction (PCR) amplifi cation of E1A. Transgenic and control animals were observed for morbidity a nd weight changes. Eleven of 45 animals were transgenic (24% efficiency) wi th an estimated 5 to 57 copies of the gene per genome. Profound weight loss (>20%) led to sacrifice or death of one of five females (at 12 weeks) and four of six males (at 16 to 17 weeks). Grossly visible tumors (2 to 10 mm) were noted in the forestomach at the visible margin between the: proximal ( squamous-lined) stomach and the distal glandular stomach. Histologic sectio ns confirmed adenocarcinoma arising in each case at the squamocolumnar junc tion with glandular formation, pleomorphism, and frequent mitotic figures. Immunostaining was positive for p53 indicating accumulation of mutated or a ltered p53 protein. E1A/E1B transgenic animals developed macroscopic and mi croscopic adenocarcinoma at the squamocolumnar junction, which corresponds to adenocarcinoma at the human esophagogastric junction. Disruption of p53 was present in the transgenic model as in the human cancer.