The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells.

Abstract

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.

• Authors: Yuexing Zhang, Xin-Wei Wang, Danijela Jelovac, Takeo Nakanishi, Myoung-Hee Yu, Damilola Akinmade, Olga Goloubeva, Douglas D Ross, Angela Brodie, Anne W Hamburger
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 28 Pg. 9890-5 (Jul 12 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15994225 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• Androgen Antagonists
• Anilides
• Carrier Proteins
• DNA Primers
• Nitriles
• PA2G4 protein, human
• RNA-Binding Proteins
• Receptors, Androgen
• Tosyl Compounds
• Cyproterone Acetate
• bicalutamide
• Luciferases
• Receptor, ErbB-3

Topics

• Adaptor Proteins, Signal Transducing
• Androgen Antagonists (metabolism)
• Anilides (metabolism)
• Animals
• Blotting, Western
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Cyproterone Acetate (metabolism)
• DNA Primers
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic
• Humans
• Luciferases
• Male
• Mice
• Mice, SCID
• Nitriles
• Oligonucleotide Array Sequence Analysis
• Prostatic Neoplasms (metabolism, therapy)
• RNA-Binding Proteins
• Receptor, ErbB-3 (metabolism)
• Receptors, Androgen (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tosyl Compounds