Esophageal cancer has become a significant health problem in the US. Tobacco smoke and gastroesophageal reflux are the most important risk factors in causing esophageal cancer. Our objective is to investigate RAR-p2 and the associated molecular pathway for developing novel strategies to prevent this now deadly disease. RAR--32 expression is progressively lost in premalignant and malignant esophageal tissues. BPDE (a carcinogen present in tobacco smoke and environmental pollution) and tumor-promoting bile acid suppressed RAR-p2 expression and induced expression of EGFR, AP-1, COX-2, and phosphorylated Erk1/2 in premalignant and malignant esophageal cells. Restoration of RAR-(32 expression suppressed esophageal cancer cell growth and induced apoptosis in vitro and tumor formation in vivo, which were correlated with decreased expression of EGFR, AP-1, and COX-2 and phosphorylated Erk1/2. Therefore, targeting these genes may translate into better control of esophageal cancer. In this proposal, we hypothesize that suppression of RAR-(32 and induction of EGFR/Erk1/2/AP-1/COX2 expression by BPDE and bile acid are important events in esophageal cancer development and progression. Reversal of these events by using a combined treatment with chemopreventive agents like EGCG, curcumin, and statins should provide an effective approach to prevent or delay esophageal carcinogenesis. To test this hypothesis, we proposed the following Specific Aims: 1). To elucidate molecular mechanisms responsible for the esophageal cancer risk factors-altered gene expression and to define a novel RAR-(32-led signaling pathway. 2). To determine the combined effects of chemoprevention agents (i.e., EGCG, curcumin, or statins) on esophageal cancer cells in vitro and in nude mice xenografts and on a rat esophageal adenocarcinoma model. Up on completion of this project, we expect to define a novel molecular pathway involving BPDE and bile acid-induced esophageal carcinogenesis, to provide a preclinical evaluation of these three agents, and to use these genes as intermediate biomarkers for clinical chemoprevention studies of these agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA117895-03
Application #
7560043
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2007-04-03
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2009
Total Cost
$249,408
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Psychology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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