inactivation of E-cadherin mediated cell - cell adhesion may play an important role in the complex process of prostate cancer metastasis. Down-regulation of E-cadherin expression correlates with high tumor grade and stage in human prostate cancers. In a small subset of patients we have shown that E-cadherin immunoreactivity is a predictor of biochemical recurrence in prostate cancer patients. However, the mechanism responsible for down-regulation of e- cadherin expression in prostate cancer cells is incompletely understood. Hypothesis: Loss of E-cadherin expression results in prostate cancer cells with increased metastatic potential. Accordingly, analysis of E- cadherin immunoreactivity will improve our ability to predict prostate cancer progression. Hypermethylation of 5' regulatory sequences is associated with loss of E-cadherin expression, and may be the molecular mechanism responsible for inactivation of E-cadherin expression in prostate cancer cells. Further, upregulation of E- cadherin expression with demethylating agents may inhibit prostate cancer progression.
Specific aims : 1) Analyze E- cadherin expression in primary human prostate cancers. Use survival analysis and a Cox proportional Hazards model to show that E- cadherin expression is an independent predictor of disease free survival. 2) use genomic sequencing to show that hypermethylation of 5' regulatory sequences is associated with down-regulation of E-cadherin gene expression. 3) Determine the temporal relationship between: (a) inactivation of E-cadherine mediated cell - cell adhesion; (b)) the development of metastasis; and (c)) hypermethylation of 5' regulatory sequences of the E-cadherin gene in a transgenic mouse model of prostate cancer. 4) Determine whether E-cadherin expression can be restored in vivo using the demethylating agent 5-aza-2'-deoxycytidine. Show that restoration of E-cadherin gene expression correlates with demethylation of 5' regulatory sequences, and reduces the metastatic capability of prostate cancer cells in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA074290-01
Application #
2012278
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1997-07-15
Project End
2002-06-30
Budget Start
1997-07-15
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Urology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030