Esophagogastric adenocarcinoma in an E1A/E1B transgenic model involves p53 disruption.
We studied tumorigenesis and p53 immunostaining in a murine transgenic model introducing E1A/E1B 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 E1B gene product interferes with p53-mediated apoptosis, inhibiting tumor suppression at the G(1)/S checkpoint. Transgenic animals were generated utilizing a purified linear 6.7 kb fragment of plasmid DNA containing MMTV-LTR/E1A/E1B and were confirmed by dot blot hybridization of tail DNA to (32)P-labeled E1A/E1B probe and polymerase chain reaction (PCR) amplification of E1A. Transgenic 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 p53 indicating accumulation of mutated or altered p53 protein. E1A/E1B 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.
Duncan
M D
MD
Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. mduncan@jhmi.edu
Tihan
T
T
Donovan
D M
DM
Phung
Q H
QH
Rowley
D L
DL
Harmon
J W
JW
Gearhart
P J
PJ
Duncan
K L
KL
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins