The ErbB3-Binding Protein Ebp1 Suppresses Androgen Receptor-Mediated Gene Transcription and Tumorigenesis of Prostate Cancer Cells
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 can...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 28; pp. 9890 - 9895 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
12.07.2005
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 To whom correspondence should be addressed at: Greenebaum Cancer Center, University of Maryland, 655 West Baltimore Street, Baltimore, MD 21201. E-mail: ahamburg@som.umaryland.edu. Author contributions: Y.Z. and A.W.H. designed research; Y.Z., D.J., T.N., M.-h.Y., D.A., and A.W.H. performed research; Y.Z., X.-W.W., D.J., T.N., D.D.R., and A.B. contributed new reagents/analytic tools; Y.Z., X.-W.W., T.N., O.G., and A.W.H. analyzed data; and Y.Z., X.-W.W., and A.W.H. wrote the paper. Communicated by Henry Lardy, University of Wisconsin, Madison, WI, May 9, 2005 Abbreviations: AR, androgen receptor; PSA, prostate-specific antigen; SCID, severe combined immunodeficient; HDAC, histone deacetylase; DHT, dihydrotestosterone; MMTV, mouse mammary tumor virus; CA, cyproterone acetate. D.J. and T.N. contributed equally to this work. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0503829102 |