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

Yuexing Zhang, Xin Wei Wang, Danijela Jelovac, Takeo Nakanishi, Myoung Hee Yu, Damilola Akinmade, Olga Goloubeva, Douglas D. Ross, Angela Brodie, Anne W. Hamburger

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)9890-9895
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number28
DOIs
StatePublished - Jul 12 2005
Externally publishedYes

Keywords

  • Androgen independence
  • Erbb receptors
  • Transcriptional corepressors

ASJC Scopus subject areas

  • General

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