The androgen receptor (AR) is central to the initiation and growth of prostate cancer and to the therapeutic response to hormones. Although the expression and activity of AR is controlled by AR coregulators, the manipulation of endogenous AR corepressors to downregulate AR levels has not been exploited therapeutically. We have demonstrated that EBP1, a protein isolated in our laboratory by its ability to bind ErbB3, is an AR corepressor that suppresses protein levels of AR and AR target genes and inhibits growth of prostate cancer cells. The ability of EBP1 to repress AR function can be regulated by the ErbB3/4 ligand heregulin (HRG) an important modulator of prostate cancer cell growth. Recent work from independent laboratories has shown that activation of the ErbB2/3 heterodimer by HRG can destabilize endogenous AR mRNA. We hypothesize that EBP1 mediates the effects of HRG by binding to and destabilizing AR mRNA in an HRG-inducible manner. Further, we postulate that the clinical efficacy of ErbB tyrosine kinase inhibitors (TKIs) has been disappointing because inhibition of ErbB activity results in abrogation of HRG-induced AR destabilization. Our preliminary and published data indicate that EBP1 modulates the growth of prostate cancer cells in response to HRG to TKIs. This grant will delineate the ability of EBP1 to affect the sensitivity of prostate cancer cells to TKIs and the role that EBP1-induced destabilization of AR plays in this response. We hypothesize that EBP1 may be a novel biomarker that can be used to identify patients that may benefit from ErbB directed therapies. The purpose of Specific Aim 1 is to elucidate the mechanism of the destabilization of AR mRNA by EBP1. These studies will a) determine the regions of interaction between EBP1 and AR mRNA in vivo and their functional significance b) determine the role of EBP1 in mediating HRG's destabilization of AR mRNA c) determine the regulation of EBP1-AR mRNA interactions in a physiological relevant setting using the Ebp1 knock out mouse model. The purpose of Specific Aim II is to determine if EBP1 status affects the ability of prostate cancer cells to respond to TKIs. We will use both in vitro and in vivo models to determine if manipulation of EBP1 levels or mutation of EBP1 can alter cellular response to TKIs. We will examine if the observed effects are regulated via EBP1-induced AR destabilization.
Hormone refractory prostate cancer is a uniformly fatal disease with a short survival time. The androgen receptor (AR) controls the growth of hormone refractory prostate cancer. This study will examine the ability of a novel AR corepressor (EBP1) to control levels of AR mRNA and ultimately prostate cancer growth.
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