The ErbB3-Binding Protein Ebp1 Suppresses Androgen Receptor-Mediated Gene Transcription and Tumorigenesis of Prostate Cancer Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 28; pp. 9890 - 9895
• Main Authors: Zhang, Yuexing, Wang, Xin-Wei, Jelovac, Danijela, Nakanishi, Takeo, Yu, Myoung-hee, Akinmade, Damilola, Goloubeva, Olga, Ross, Douglas D., Brodie, Angela, Hamburger, Anne W., Lardy, Henry
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.07.2005; National Acad Sciences
• Subjects: Adaptor Proteins, Signal Transducing; Androgen antagonists; Androgen Antagonists - metabolism; Androgens; Anilides - metabolism; Animals; Biological Sciences; Blotting, Western; Carrier Proteins - metabolism; Cell growth; Cell Line, Tumor; Cells; Chromatin Immunoprecipitation; Cyproterone Acetate - metabolism; Directional control; DNA Primers; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Genes; Heterologous transplantation; Humans; Luciferases; Male; Medical treatment; Messenger RNA; Mice; Mice, SCID; Nitriles; Oligonucleotide Array Sequence Analysis; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - therapy; Proteins; Receptor, ErbB-3 - metabolism; Receptors, Androgen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins; Tosyl Compounds; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0503829102

Down-regulation of the androgen receptor (AR) is being evaluated as an effective therapy for the advanced stages of prostate cancer. We report that Ebp1, a protein identified by its interactions with the ErbB3 receptor, down-regulates expression of AR and AR-regulated genes in the LNCaP prostate cancer cell line. Using microarray analysis, we identified six endogenous AR target genes, including the AR itself, that are down-regulated by ebp1 overexpression. Chromatin immunoprecipitation assays revealed that Ebp1 was recruited to the prostate-specific antigen gene promoter in response to the androgen antagonist bicalutamide, suggesting that Ebp1 directly affected the expression of AR-regulated genes in response to androgen antagonists. Ebp1 expression was reduced in cells that had become androgen-independent. Androgens failed to stimulate either the growth of ebp1 transfectants or transcription of AR-regulated reporter genes in these cells. The agonist activity of the antiandrogen cyproterone acetate was abolished in ebp1 transfectants. In severe combined immunodeficient mice, Ebp1 overexpression resulted in a reduced incidence of LNCaP tumors and slower tumor growth. These findings suggest that Ebp1 is a previously unrecognized therapeutic target for treatment of hormone refractory prostate cancer.