ENDOTHELIN B RECEPTOR AND PROSTATE CANCER

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DESCRIPTION (Applicant's Description): Prostate cancer is the second most common cause of death from cancer in U.S. men. Effective treatment of advanced disease demands a better understanding of prostate cancer tumor biology. Dr. Joel B. Nelson aspires to a career of independent research producing those insights which lead to useful therapy for prostate cancer. Therefore, the mutually inclusive objectives of this application are 1) to support the development of an outstanding clinician research scientist, and 2) to investigate the endothelin B receptor (ETB) as potential human prostate cancer tumor suppressor. This mentored research award will provide Dr. Joel B. Nelson with a vehicle for training in the molecular biology, signal transduction and receptor pharmacology of human prostate cancer at the Brady Urological Institute Research Laboratories of the Johns Hopkins University School of Medicine, under Dr. William G. Nelson, the award sponsor. The predominant endothelin receptor on benign prostate epithelial cells, ETB is greatly reduced in prostate cancer and is associated with somatic hypermethylation of CpG dinucleotide sequences in the 5' region of the ETB gene in over 60% of the prostate cancers studied. The ETB receptor has unique functions, including ligand clearance, inhibition of endothelin-1 secretion, and activation of counterregulatory pathways. This project is designed to investigate the hypothesis that loss of ETB function in prostate cancer directly contributes to carcinogenesis, progression and morbidity. To test the hypothesis that loss of ETB expression is a critical step in prostate carcinogenesis, ETB expression will be reconstituted in prostatic carcinoma cell lines via stable transfection of ETB-encoding cDNA constructs. ETB expressing subclones will be assessed for growth potential, tumorigenicity, and phenotypic selection. To test the hypothesis that loss of ETB expression in prostate cancer causes local ET axis deregulation, the regulation of ET-1 expression and production in prostatic cell lines which express the ETB receptor will be studied. To test the hypothesis that loss of ETB expression results in the loss of critical ETB mediated secondary messenger pathways, several signaling cascades will be studied in both normal and malignant prostate tissues. To test the hypothesis that loss of ETB expression can result from ETB gene mutations, determination of ETB mRNA expression by in situ hybridization will be coupled with ETB mutation analysis. The broad approach to this evolving question in prostate cancer tumor biology will provide an excellent training experience and novel insights.