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 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.
Zhang
Yuexing
Y
Greenebaum Cancer Center and Departments of Pathology and Pharmacology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Wang
Xin-Wei
XW
Jelovac
Danijela
D
Nakanishi
Takeo
T
Yu
Myoung-Hee
MH
Akinmade
Damilola
D
Goloubeva
Olga
O
Ross
Douglas D
DD
Brodie
Angela
A
Hamburger
Anne W
AW
D048868:Adaptor Proteins, Signal Transducing; D000726:Androgen Antagonists / Q000378:metabolism; D000813:Anilides / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017373:Cyproterone Acetate / Q000378:metabolism; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008156:Luciferases; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009570:Nitriles; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000628:therapy; D016601:RNA-Binding Proteins; D020893:Receptor, ErbB-3 / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds
D048868:Adaptor Proteins, Signal Transducing; D000726:Androgen Antagonists; D000813:Anilides; D002352:Carrier Proteins; D017931:DNA Primers; D009570:Nitriles; C101633:PA2G4 protein, human; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D017373:Cyproterone Acetate; C053541:bicalutamide; D008156:Luciferases; D020893:Receptor, ErbB-3