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 evaluatedas 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 ARregulated 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.ErbB receptors ͉ transcriptional corepressors ͉ androgen independence

Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells

“…Cell growth measurement in complete media was performed using a hemocytometer (Zhang et al, 2005). To assess the effect of steroid DHT on cell growth, cells (2 Â 10 4 ) were plated in 12-well plates in the presence of 100 nM DHT (unless indicated otherwise).…”

The ERBB3 receptor in cancer and cancer gene therapy

“…Further study is needed of the involvement of non-NRG, non-ERBB regulators of ERBB3, such as CDK5, [122][123][124] BRK, 125 SRC, 126 and MET. 120 The fascinating and widely expressed ERBB3 effector EBP1 has thus far been examined mainly in mammary and prostate cells; [154][155][156][157][158][159][160][161][162][163][164] may it be important also in other cancers where ERBB3 is clearly a player, such as lung and melanoma? It is hoped that full understanding of the regulation and functions of ERBB3 will facilitate its integration into cancer management.…”

“…157,[159][160][161][162] EBP1 contains an LXXLL motif mediating interactions with nuclear hormone receptors and binds androgen receptor, resulting in inhibition of activation of androgen-responsive gene promoters. 157,163,164 Transcriptional effects of EBP1 are dependent on phosphorylation at serine 363. 165 Thus, in both breast and prostate cancer cells, EBP1 is potentially a critical effector for ERBB3 signaling.…”

“…Among the several known effects of the freed EBP1 is interaction with the androgen receptor as an inhibitor, so in androgen-dependent prostate cancer cells EBP1 suppressed proliferation and xenograft growth, in part by blocking androgen action. [162][163][164] Thus in such cells there is theoretical possibility of opposite effects of NRG activation of ERBB3: activation of the androgen receptor and its effects via AKT-dependent and -independent actions, and inhibition of it via EBP1. It is not surprising that variable effects have been seen experimentally with NRG applied to prostate cancer cells.…”

“…271 Expression of mRNAs for TGFα, as well as for amphiregulin, heparin-binding EGF and epiregulin, were 10-to 100-fold greater in androgen-independent DU145 and PC3 cells, compared with hormone-responsive LNCaP and PNT1A cells. 272 In addition, low levels of EBP1 in androgen-independent prostate cancer cells 164 could contribute to constitutive upregulation of androgen receptor-controlled events.…”