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.
Greenebaum Cancer Center and Departments of Pathology and Pharmacology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Yuexing
Y
Zhang
Xin-Wei
XW
Wang
Danijela
D
Jelovac
Takeo
T
Nakanishi
Myoung-Hee
MH
Yu
Damilola
D
Akinmade
Olga
O
Goloubeva
Douglas D
DD
Ross
Angela
A
Brodie
Anne W
AW
Hamburger
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