Esophagogastric adenocarcinoma in an E1A/E1B transgenic model involves p53 disruption

We studied tumorigenesis and p53 immunostaining in a murine transgenic model introducing ElA/ElB under the control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter in which adenocarcinoma occurs at the squamocolumnar junction in the foregut, predominantly in males, and at no other site. Mutations of p53 are frequent in human esophageal adenocarcinoma and the ElB gene product interferes with p53-mediated apoptosis, inhibiting tumor suppression at the G1/S check-point. Transgenic animals were generated utilizing a purified linear 6.7 kb fragment of plasmid DNA containing MMTV-LTR/ElA/ElB and were confirmed by dot blot hybridization of tail DNA to 32P-labeled E1A/E1B probe and polymerase chain reaction (PCR) amplification of ElA. T’ransgenic and control animals were observed for morbidity and weight changes. Eleven of 45 animals were transgenic (24% efficiency) with 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 sections confirmed adenocarcinoma arising in each case at the squamocolumnar junction with glandular formation, pleomorphism, and frequent mitotic figures. Immunostaining was positive for pS3 indicating accumulation of mutated or altered p53 protein. ElA/ElB transgenic animals developed macroscopic and microscopic 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.