The goal of this project is to elucidate detailed genetic information driving tumorigenesis at the squamocolumnar junction in a murine transgenic model to allow development of effective therapies for esophageal adenocarcinoma, the most rapidly rising malignancy in humans. We have engineered mice to express the E1A and E1B genes under the control of the MMTV-LTR promoter. The transgenic mice develop adenocarcinoma at the squamocolumnar junction in the forestomach, predominantly in males, and at no other site. We have demonstrated immunostaining for both androgen receptor and p53 in the tumors. The human anatomical correlate of the squamocolumnar junction is at the esophago- gastric junction. The MMTV-LTR promoter used in this model is not otherwise site specific for the stomach. We will examine transgene transcription on a microscopic level to determine which specific tissues at or near the squamocolumnar junction express the transgene. Anatomic distribution of E1A/E1B expression will be confirmed by in-situ hybridization. E1A and E1B are known to affect G1/S cell cycle checkpoint proteins including the retinoblastoma gene product and E2F transcription, cyclins, and mediators of apoptosis p53 and p21. Disruption of similar genetic pathways by alterations or mutations in p53, EGFR, TGFalpha, and cyclins are implicated in Barrett's and esophageal adenocarcinoma. We will examine these target gene products by immunohistochemistry. Proliferation will be assayed by Ki67 staining. We will examine the p53 gene for mutations by cloning and sequencing. To study site specificity and male predominance of the tumors, hormone receptor status will be determined immunohistochemically at the squamocolumnar junction and in adjacent tissue. Neutered and androgen treated animals will be compared for E1A/E1B expression together with incidence and rate of tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA076034-06
Application #
6845136
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2000-05-01
Project End
2007-04-30
Budget Start
2005-09-30
Budget End
2007-04-30
Support Year
6
Fiscal Year
2005
Total Cost
$56,728
Indirect Cost
Name
Johns Hopkins University
Department
Surgery
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218