Interrogating androgen receptor function in recurrent prostate cancer

Departments of Biological Chemistry, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
Cancer Research (Impact Factor: 9.33). 09/2003; 63(15):4552-60.
Source: PubMed


The early androgen-dependent (AD) phase of prostate cancer is dependent on the androgen receptor (AR). However, it is unclear whether AR is fully functional in recurrent prostate cancer after androgen withdrawal. To address this issue we interrogated AR signaling in AD and recurrent prostate cancer xenografts using molecular imaging, chromatin immunoprecipitation, and immunohistochemistry. In the imaging experiments, an adenovirus bearing a two-step transcriptional activation cassette, which amplifies AR-dependent firefly luciferase reporter gene activity, was injected into tumors implanted into severe combined immunodeficiency mice. A charge-coupled device optical imaging system detected the initial loss and then resumption of AR transcriptional activity in D-luciferin-injected mice as tumors transitioned from AD to recurrent growth. The results of chromatin immunoprecipitation and immunohistochemical localization experiments correlated with the Ad two-step transcriptional activation imaging signal. AR localized to the nucleus and bound to the endogenous prostate-specific antigen enhancer in AD tumors but exited the nucleus and dissociated from the enhancer upon castration. However, AR reentered the nucleus and rebound the prostate-specific antigen enhancer as the cancer transitioned into the recurrent phase. Surprisingly, RNA polymerase II and the general factor TFIIB remained bound to the gene throughout the transition. Our data support the concept that AR is fully functional in recurrent cancer and suggest a model by which a poised but largely inactive transcription complex facilitates reactivation by AR at castrate levels of ligand.

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    • "AR activation under castrated conditions is thought to be the major mechanism leading to prostate cancer progression to castration resistance [6] [7]. Thus, abnormal AR nuclear localization in the absence of androgens may represent a key step leading to castration resistance [13] [14] [15] [16]. AR transactivation of downstream genes in castration-resistant prostate cancer cells requires its nuclear localization under castration conditions. "
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    ABSTRACT: Nucleocytoplasmic trafficking of the androgen receptor (AR) represents an essential step in androgen action. To determine whether the amino-terminal domain (NTD) contains potential nuclear import and/or export signals, deletion mutants of the NTD tagged with green fluorescent protein (GFP) were generated and tested for their intracellular localization in both AR-negative and AR-positive cell lines. Subcellular localization analysis suggested a role of the NTD in regulating AR subcellular localization and revealed that the region of a.a. 50-250 of the NTD of AR (AR(50-250)) could promote cytoplasmic localization. Leptomycin B inhibited the activity of AR(50-250), suggesting that AR(50-250) export is mediated through exportin 1, either directly or indirectly. These observations argue for an important role of the NTD in regulating AR nucleocytoplasmic trafficking and will facilitate further investigation of interactions among different signals in regulating AR nucleocytoplasmic trafficking, which may lead to new approaches to inhibit AR nuclear localization.
    The Journal of Steroid Biochemistry and Molecular Biology 10/2013; DOI:10.1016/j.jsbmb.2013.09.013 · 3.63 Impact Factor
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    • "Notably, during cancer progression, androgen receptor (AR) undergoes androgen-independent nuclear import through a mechanism involving MAPK pathway activation (Zhang et al. 2003). Estradiol activation of PI3-K/Akt (protein kinase B) pathway regulates estradiol receptor (ER) alpha nuclear export and cell cycle progression in MCF-7 cells (Lombardi et al. 2008). "
    Dataset: JCCS 2010

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    • "Gene microarray study of seven different human prostate cancer xenograft models demonstrated that increase of AR mRNA is the only change consistently associated with the development of androgen-independency phenotype following androgen ablation therapy, and elevation of AR mRNA and protein are both necessary and sufficient progression of prostate cancer towards androgen-independency (Culig et al 1999, Joly-Pharaboz et al 1995). Elevated AR expression in androgen-independent prostate cancer cells or recurrent hormone-refractory tumors has been observed in our progression model (Chuu et al 2005, Chuu et al 2006, Kokontis et al 1994, Kokontis et al 1998, Kokontis et al 2005, Umekita et al 1996) and several other groups (Chen et al 2004a, de Vere White et al 1997, Edwards et al 2003, Ford et al 2003, Gregory et al 2001, Hara et al 2003, Holzbeierlein et al 2004, Kim et al 2002, Linja et al 2001, Shi et al 2004, Singh et al 2004, Visakorpi et al 1995, Wang et al 2001, Zhang et al 2003). Mechanisms contribute to the progression towards androgenindependency including AR gene amplification, AR mutation, bypass of androgenic activation of AR, or bypass AR signaling for cell survival and proliferation (Feldman and Feldman 2001). "

    Prostate Cancer - Original Scientific Reports and Case Studies, 11/2011; , ISBN: 978-953-307-342-2
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