Abstract
Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10–20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression.
Introduction
The androgen/androgen receptor (AR) signaling pathway is known to play a critical role in prostate tumorigenesis and prostate cancer (PCa) progression. Androgen-deprivation therapy (ADT) either reduces the production of androgens by surgical or medical castration, or interferes with the activity of the AR through the use of anti-androgens (Miyamoto et al. 2004). ADT is initially effective in about 90% of PCa cases, but these eventually circumvent ADT and emerge as castration-resistant PCa (CRPC; Roy-Burman et al. 2005). However, the androgen/AR signaling pathway remains a key determinant of cell proliferation in CRPC, despite low levels of available androgens following ADT (Litvinov et al. 2003). The reactivation of the androgen/AR signaling pathway in CRPC has been attributed to a number of mechanisms, including AR hypersensitivity, local intracrine production of androgens, promiscuous activation of the AR by adrenal androgens, non-androgenic steroids and even anti-androgens, and activation of the AR by growth factors and cytokines (Debes & Tindall 2004, Titus et al. 2005). These phenomena may result from abnormalities of the AR itself (AR mutation and overexpression) and/or its related molecules (AR cofactors). Furthermore, several kinds of AR splice variants displaying significant constitutive activity in the absence of ligand-binding have recently been reported by several laboratories (Dehm et al. 2008, Guo et al. 2009, Hu et al. 2009, Sun et al. 2010). Many studies have shown that progression to CRPC is associated with AR overexpression, and that AR inhibition represses tumor growth in PCa, even in CRPC (Gregory et al. 1998, Zegarra-Moro et al. 2002, Chen et al. 2004a,b, Scher & Sawyers 2005). Less than 10% of CRPC cases were found to possess somatic AR gene mutations (Taplin et al. 2003). In addition, the AR is upregulated in most CRPCs, of which only 10–20% exhibit amplification of the AR gene (Linja et al. 2001), indicating that increased AR expression in CRPC may result from factors other than gene amplification. The molecular mechanisms underpinning the aberrant AR expression have thus been intensively investigated as a potential source of novel therapeutic targets.
Although the expression of proteins, including AR protein, is regulated by various steps (transcription, translation, and post-translational control), the transcriptional step is generally thought to play a critical role in gene expression. In addition, AR overexpression has been detected at both the protein and mRNA levels in CRPC, suggesting that transcriptional regulation of the AR gene is at least one of the major causes of AR dysregulation. In this review, we therefore summarize the factors involved in AR expression, with an emphasis on transcriptional regulation by transcription factors in PCa (Table 1). Furthermore, we also discuss the therapeutic potential of targeting AR expression for the treatment of PCa and CRPC, by considering the agents involved in the regulation of AR expression (Table 2).
Transcription factor-related factors regulating human androgen receptor (AR) expression in prostate cancer
| Factor | Gene classification | Gene function | Cells | Effect | Direct or indirect | Supposed mechanism | References |
|---|---|---|---|---|---|---|---|
| CREB | Transcription factor | Induction of genes in response to hormonal stimulation of the cAMP pathway | LNCaP | + | Direct | Binding to CRE site | Mizokami et al. (1994) |
| Myc | Transcription factor | Cell cycle progression, apoptosis, and cellular transformation | Vitro | + | Direct | Binding to E-box | Grad et al. (1999) |
| Myc | Transcription factor | Cell cycle progression, apoptosis, and cellular transformation | LNCaP | + | Indirect | Binding to E-box | Lee et al. (2009) |
| c-Jun | Transcription factor | Transforming gene | LNCaP | − | Direct | Binding to TRE site | Pan et al. (2003) |
| c-Jun | Transcription factor | Transforming gene | LNCaP | − | Direct | Binding to TRE site | Yuan et al. (2004) |
| Sp1 | Transcription factor | Constitutive induction of genes | Vitro | + | Direct | Binding to GC-box | Faber et al. (1993) |
| Sp1 | Transcription factor | Constitutive induction of genes | LNCaP | + | Direct | Binding to GC-box | Yuan et al. (2005) |
| p53 | Transcription factor | Cell cycle arrest, apoptosis, senescence, DNA repair, and metabolism | LNCaP | − | Direct | Binding to p53-binding site | Alimirah et al. (2007) |
| Foxo3a | Transcription factor | Trigger for apoptosis | LNCaP | + | Direct | Binding to Foxo-response element | Yang et al. (2005) |
| LEF1 | Transcription factor | Hair cell differentiation, follicle morphogenesis, and cellular transformation | LNCaP | + | Direct | Binding to LEF/TCF-binding site | Yang et al. (2006) |
| LEF1 | Transcription factor | Hair cell differentiation, follicle morphogenesis, and cellular transformation | LNCaP, AI-LNCaP | + | Direct | Binding to LEF/TCF-binding site | Li et al. (2009) |
| Wnt-1 | Cytokine | Oncogenesis and developmental processes | LNCaP | + | Indirect | Activation of β-catenin | Yang et al. (2006) |
| β-Catenin | Signal transduction | Cell growth and adhesion | LNCaP | + | Direct | Activation of LEF1 and LEF1 complex | Yang et al. (2006) |
| Purα | Transcription factor | DNA replication and transcription | LNCaP, AI-LNCaP | − | Direct | Binding to suppressor element (ARS) binding sites | Wang et al. (2008) |
| NFκB | Transcription factor | Cellular transformation and inflammation | LNCaP | + | Direct | Binding to NFκB-binding site | Zhang et al. (2009) |
| Twist1 | Transcription factor | Differentiation, epithelial– mesenchymal transition | LNCaP, 22Rv1, CxR | + | Direct | Binding to E-box | Shiota et al. (2010) |
| E2F1 | Transcription factor | Cell cycle progression | LNCaP | − | Direct | Binding to E2F-binding site | Davis et al. (2006) |
| E2F1, E2F3 | Transcription factor | Cell cycle progression | LNCaP | + | Direct | Binding to E2F-binding site | Sharma et al. (2010) |
| Rb1 | Transcription cofactor | Cell cycle arrest and tumor suppressor | LNCaP, LAPC-4 | − | Direct | Inhibition of E2F1 transactivation | Sharma et al. (2010) |
| SREBP-1 | Transcription factor | Sterol biosynthesis | LNCaP, C4-2 | + | Direct | Binding to sterol regulatory element | Huang et al. (2010) |
| β2-Microglobulin | Membrane protein | Endocytosis of iron | LNCaP, C4-2 | + | Indirect | Activation of SREBP-1 | Huang et al. (2010) |
| Interleukin-8 | Cytokine | Inflammation | LNCaP, 22Rv1 | + | Indirect | Activation of NFκB and AP-1 | Seaton et al. (2008) |
| Endothelin-1 | Hormone | Vasoconstrictor | LNCaP | + | Indirect | Activation of Myc | Lee et al. (2009) |
| HB-EGF | Growth factor | Mitogenic factor (ErbB1 agonist) | LNCaP | − | Indirect | Inhibition of AR transcription | Adam et al. (2002) |
| Activin A | Growth factor | TGF-β superfamily | LNCaP | + | Indirect | Activation of Smads | Kang et al. (2009) |
| Smad2, 3 | Signal transduction | Cell proliferation, apoptosis, and differentiation | LNCaP | + | Direct | Activation of AR transcription | Kang et al. (2009) |
| Nemo-like kinase (NLK) | Kinase | MAPK-like kinase | LNCaP | − | Indirect | Inhibition of LEF1 and LEF1 complex | Emami et al. (2009) |
| ErbB3-binding protein 1 (EBP1) | RNA-binding protein | Growth regulation and differentiation | LNCaP | − | Direct | Inhibition of AR transactivation | Zhang et al. (2005) |
| Angiotensin II type 1 | Hormone | Vasoconstrictor | LNCaP | + | Indirect | Activation of NFκB and c-myc | Hoshino et al. (2010) |
| AT1R | Receptor | Vasoconstrictor | LNCaP | + | Indirect | Activation of NFκB and c-myc | Hoshino et al. (2010) |
+/−, up/downregulation of androgen receptor.
Agents involved in androgen receptor expression
| Small molecule | Major function | Cells | Effect | Action level | Supposed mechanism | References |
|---|---|---|---|---|---|---|
| Natural compounds | ||||||
| EGCG | Polyphenol | LNCaP | − | Transcription | Inhibition of Sp1 | Ren et al. (2000) |
| Theaflavin-3,3′-digallate (TF3) | Polyphenol | LNCaP | − | Post-translational | Inhibition of rat liver microsomal 5α-reductase activity | Lee et al. (2004) |
| Penta-O-galloy-β-d-glucose (5GG) | Polyphenol | LNCaP | − | Post-translational | Inhibition of rat liver microsomal 5α-reductase activity | Lee et al. (2004) |
| Quercetin | Polyphenol | LNCaP | − | Transcription | NA | Xing et al. (2001) |
| Quercetin | Polyphenol | LNCaP | − | Transcription | Activation of c-Jun | Yuan et al. (2004) |
| Resverol | Polyphenol | LNCaP | − | Transcription | Activation of c-Jun | Yuan et al. (2004) |
| Quercetin | Polyphenol | LNCaP | − | Transcription | Inhibition of Sp1 | Yuan et al. (2005) |
| Genistein combined polysaccharide (GCP) | Polyphenol | LNCaP | − | Non-transcription | NA | Tepper et al. (2007) |
| Leteolin (3′,4′,5,7-tetrahydroxyflavone) | Polyphenol | LNCaP | − | Transcription | NA | Chiu & Lin (2008) |
| Indole-3-carbinol | Compound found in vegetables | LNCaP | − | Transcription | NA | Hsu et al. (2005) |
| Phenethyl isothiocyanate (PEITC) | Compound found in vegetables | LNCaP | − | Transcription | Inhibition of Sp1 | Wang et al. (2006) |
| d,l-sulforaphane (SFN) | Compound found in vegetables | LNCaP, C4-2 | − | Transcription | NA | Su-Hyeong & Shivendra (2009) |
| Baicalin | Polyphenol (component of PC-SPES) | LNCaP | − | NA | NA | Chen et al. (2001) |
| Baicalein | Polyphenol (component of PC-SPES) | LNCaP | − | NA | NA | Chen et al. (2001) |
| Thymoquinone | Component of herbs | LNCaP, C4-2 | − | NA | NA | Kaseb et al. (2007) |
| Gum mastic | Natural resin | LNCaP | − | Transcription | NA | He et al. (2006) |
| Acetyl-11-keto-β-boswellic acid (AKBA) | Natural resin | LNCaP | − | Transcription | Inhibition of Sp1 | Yuan et al. (2008) |
| Selenium | ||||||
| Methylselenocysteine (MSC) | Organic selenium-containing compounds | LNCaP | − | NA | NA | Lee et al. (2006) |
| Methylseleninic acid (MSA) | Organic selenium-containing compounds | LNCaP | − | Transcription | NA | Chun et al. (2006) |
| 1,4-Phenylenebis(methylene) selenocyanate | Organic selenium-containing compounds | LNCaP, C4-2 | − | NA | NA | Nicole et al. (2010) |
| Methylseleninic acid (MSeA) | Organic selenium-containing compounds | LNCaP, LAPC-4 | − | Transcription | Inhibition of Sp1 | Husbeck et al. (2006) |
| Selenite | Nonorganic selenium-containing compounds | LNCaP, LAPC-4 | − | Transcription | Inhibition of Sp1 | Husbeck et al. (2006) |
| Hormones and vitamins | ||||||
| Androgen | Androgen | LNCaP | − | Transcription | NA | Brinkmann et al. (1989) |
| DHT | Androgen | LNCaP | + | Transcription | Activation of Myc | Lee et al. (2009) |
| R1881 | Synthetic androgen | LNCaP | − | Transcription | NA | Ravenna et al. (1995) |
| Hydroxy-flutamide (OH-FLU) | Anti-androgen | LNCaP | − | Transcription | NA | Ravenna et al. (1995) |
| Fulvestrant (ICI 182 780) | Anti-estrogen | LNCaP | − | Transcription | NA | Bhattacharyya et al. (2006) |
| 1,1-bis(3′-indolyl)-1-(p-substitutedphenyl) methanes (C-DIMs) | PPARγ agonists | LNCaP | − | Transcription | PPARγ-independent pathway | Chintharlapalli et al. (2007) |
| 9-cis retinoic acid | Retinoic acid | LNCaP | + | Transcription | NA | Zhao et al. (1999) |
| 1α,25-Dihydroxyvitamin D3 | Vitamin | LNCaP | + | Transcription | NA | Zhao et al. (1999) |
| α-Tocopheryl succinate (vitamin E succinate, VES) | Vitamin | LNCaP | − | Transcription | Inhibition of Sp1 | Huang et al. (2009) |
| TS-1 (derivative of VES) | Vitamin | LNCaP | − | Transcription | Inhibition of Sp1 | Huang et al. (2009) |
| Signal transduction | ||||||
| cAMP | Signal transduction | LNCaP | + | Transcription | Activation of CREB | Mizokami et al. (1994) |
| A23187 | Calcium ionophore | LNCaP | − | Transcription | Protein kinase C- or calmodulin-dependent pathways | Gong et al. (1995) |
| Thapsigargin | Intracellular endoplasmic reticulum Ca(2+)-ATPase inhibitor | LNCaP | − | Transcription | Protein kinase C- or calmodulin-dependent pathways | Gong et al. (1995) |
| Thapsigargin and its analogues | Intracellular endoplasmic reticulum Ca(2+)-ATPase inhibitor | LNCaP, LAPC-4, VCaP, MDA-Pca-2b, 22Rv1 | − | Translation | NA | Vander Griend et al. (2009) |
| Celecoxib | COX2 inhibitor | LNCaP | − | Transcription | Activation of c-Jun | Pan et al. (2003) |
| Nimesulide | COX2 inhibitor | LNCaP | − | Transcription | Activation of c-Jun | Pan et al. (2003) |
| Sulindac sulfide | Non-steroidal anti-inflammatory drug | LNCaP | − | Transcription | Activation of c-Jun, inhibition of Sp1, NF1 and CREB | Lim et al. (2003) |
| Sulindac sulfone (exisulind) | Non-steroidal anti-inflammatory drug | LNCaP | − | Transcription | Activation of c-Jun, inhibition of Sp1, NF1 and CREB | Lim et al. (2003) |
| CP248 | Potent analogs of exisulind | LNCaP | − | Transcription | Activation of c-Jun, inhibition of Sp1, NF1 and CREB | Lim et al. (2003) |
| CP461 | Potent analogs of exisulind | LNCaP | − | Transcription | Activation of c-Jun, inhibition of Sp1, NF1 and CREB | Lim et al. (2003) |
| Trichostatin A (TSA) | HDAC inhibitor | AI-LNCaP | − | Transcription | Restoring suppressor element (ARS)-binding complex | Wang et al. (2004) |
| Trichostatin A (TSA) | HDAC inhibitor | LNCaP | − | Transcription | NA | Rokhlin et al. (2006) |
| Suberohydroxamic acid | HDAC inhibitor | LNCaP | − | Transcription? | NA | Rokhlin et al. (2006) |
| Depsipeptide | HDAC inhibitor | LNCaP | − | Transcription? | NA | Rokhlin et al. (2006) |
| Sodium butyrate | HDAC inhibitor | LNCaP | − | Transcription? | NA | Rokhlin et al. (2006) |
| Sodium butyrate | HDAC inhibitor | LNCaP | + | NA | NA | Kim et al. (2007) |
| Suberoylanilide hydroxamic acid (SAHA, vorinostat) | HDAC inhibitor | LNCaP | − | Transcription | NA | Marrocco et al. (2007) |
| Parthenolide | NFκB inhibitor | LNCaP, 22Rv1 | − | Transcription | Inhibition of NFκB | Zhang et al. (2009) |
| AZ10397767a | CXC-chemokine receptor-2 inhibitor | LNCaP | − | Transcription | Inhibition of IL8 receptor | Seaton et al. (2008) |
| BAY11-7082a | NFκB inhibitor | LNCaP | − | Transcription | Inhibition of NFκB induced by IL8 | Seaton et al. (2008) |
| JNK inhibitor Ia | JNK inhibitor | LNCaP | − | Transcription | Inhibition of AP-1 | Seaton et al. (2008) |
| Others | ||||||
| Doxorubicin | Anticancer drug (anthracyclin) | LNCaP | − | NA | NA | Rokhlin et al. (2006) |
| Etoposide | Anticancer drug (topoisomerase II inhibitor) | LNCaP | − | Transcription | NA | Liu & Yamauchi (2010) |
| Anti-β2-microglobulin polyclonal antibody | Antibody | LNCaP, C4-2 | − | Transcription | NA | Huang et al. (2008) |
| Anti-β2-microglobulin monoclonal antibody | Antibody | LNCaP, C4-2 | − | Transcription | Inhibition of SREBP-1 | Huang et al. (2010) |
| Resveratol | Phytoalexin | LNCaP | − | Transcription | NA | Mitchell et al. (1999) |
| Nigerincan | Antibiotic | LNCaP, 22Rv1 | − | Transcription | NA | Mashima et al. (2010) |
| Clioquinol (CQ) | Therapeutic agent for Alzheimer's disease | LNCaP, C4-2 | − | NA | NA | Chen et al. (2007) |
| Dibenzoylmethane | β3-Diketone | LNCaP | − | Transcription | NA | Jackson et al. (2007) |
| Functional domain of saposin C | Neurotrophic peptide | LNCaP | + | Transcription | NA | Ding et al. (2007) |
| 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole | Triazole derivative | LNCaP | − | Transcription | NA | Loiarro et al. (2011) |
NA, not available.
When IL8 was added to serum-free media; +/−, up/downregulation of androgen receptor.
Transcriptional regulation
Transcriptional control is thought to play a key role in the expression of a wide variety of genes, including AR. Transcription factors bind to DNA in a sequence-specific manner for each transcription factor, and positively or negatively affect gene expression through the control of transcription. The human AR is encoded by a single copy gene located on the X-chromosome. Two major mRNAs of 11 and 7.5 kb are transcribed from this gene, regulated by cis-acting elements in its promoter region. The human AR promoter region lacks a TATA-box and a CCAAT-box, and the binding sites for several transcription factors have been mapped (Tilley et al. 1990, Faber et al. 1991, 1993, Mizokami et al. 1994, Takane & McPhaul 1996). Several transcription factors have been reported to be responsible for controlling AR transcription. We discuss the relevance of these individual transcription factors in regulating AR expression, and in PCa.
cAMP response element-binding
cAMP response element-binding (CREB) is a transcription factor that binds to the cAMP response element (CRE, 5′-TGACGTGA-3′), thereby increasing or decreasing the transcription of its target genes. Several lines of evidence suggest that CREB is a proto-oncogene (Siu & Jin 2007).
Mizokami et al. (1994) isolated a 2.3-kb AR gene promoter region and analyzed it using a chloramphenicol acetyltransferase (CAT) assay. They found that the CRE was located between −530 and −380 bp from the transcription start site (TSS), and that AR transcription was increased by cAMP. They therefore suggested that the CREB transcription factor positively regulated AR transcription, although these results need to be confirmed using modern techniques.
The active form of phosphorylated CREB has been reported to be significantly increased in bone metastatic PCa. In addition, a PCa progression model demonstrating epithelial–mesenchymal transition (EMT) also showed an increase of CREB phosphorylation associated with progression (Wu et al. 2007), and CREB-regulated transcription has recently been reported to induce neuroendocrine-like differentiation (Deng et al. 2008). Thus, CREB may promote the pathogenesis of PCa through controlling the expression of AR and other target genes.
Myc
The Myc gene, located on chromosome 8, encodes a transcription factor that regulates the expression of its target genes by binding to an enhancer sequence (E-box, 5′-CAC(A/G)TG-3′) (Adhikary & Eilers 2005). Mutated Myc genes that are persistently expressed are found in many cancers, resulting in the aberrant expression of many genes involved in cell proliferation, and subsequent cancer formation; t(8;14) is a common translocation that is involved in the development of Burkitt's lymphoma (Boxer & Dang 2001). In contrast, numerous studies have demonstrated that inhibition of Myc leads to growth retardation and cell death in many cancers, making it a potential target for anti-cancer drugs (Hermeking 2003).
Myc has been found to be involved in AR transcriptional expression. Using a reporter gene assay in AR-nonexpressing PC-3 cells, Grad et al. (1999) showed that Myc positively regulated AR transcription by binding to the E-box region. This finding was supported by the results of a study indicating that the introduction of a mutation into the E-box in the AR promoter region decreased its transcription, as measured by CAT assay (Takane & McPhaul 1996). Recently, in a more definitive manner, Myc was proven to regulate AR transcription in LNCaP cells that express AR, and are the standard cell line used as a model for androgen-dependent PCa (Lee et al. 2009).
Myc is a well-known proto-oncogene, and many associations between Myc and oncogenesis have been reported in PCa. Elevated Myc expression in primary prostate tumors was recently reported to be a predictor of biochemical recurrence after radical prostatectomy (Hawksworth et al. 2010), which is consistent with the finding that higher AR expression is a predictor of poor outcome in patients treated with radical prostatectomy (Li et al. 2004, Rosner et al. 2007). Similarly, a recent study found that increased Myc gene copy number correlated with higher Gleason score (Chen et al. 2010), while Myc overexpression reduced the expression of the tumor-suppressor gene Nkx3.1 and induced prostate cellular transformation in a mouse model (Iwata et al. 2010).
c-Jun
c-Jun is a member of the activator protein-1 (AP-1) transcription complex, which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF, and JDP families. AP-1 upregulates the transcription of genes containing the tetradecanoylphorbol 13-acetate-responsive element (TRE; 5′-TGA(G/C)TCA-3′) (Hess et al. 2004), and regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stresses, and infections (Hess et al. 2004). AP-1 in turn controls a number of cellular processes, including differentiation, proliferation, and apoptosis (Ameyar et al. 2003).
c-Jun was reported to suppress AR transcription in a reporter gene assay using the AR promoter region in LNCaP cells (Pan et al. 2003). Similarly, the same group used a gel-shift assay to show that c-Jun bound to the TRE in the AR promoter region and repressed AR transcription (Yuan et al. 2004).
Although c-Jun is known to suppress AR expression, it also functions as an AR coactivator (Bubulya et al. 2000, Chen et al. 2006). Consistent with this notion, c-Jun is highly expressed in PCa tissues, compared with benign prostate hypertrophy tissues (Tiniakos et al. 2006). Similarly, patients with high expression levels of the active form of phosphorylated c-Jun had significantly shorter relapse-free survival times, compared with patients with low phosphorylated c-Jun protein expression, suggesting that increased active-c-Jun levels may promote castration-resistant tumor growth (Edwards et al. 2004). c-Jun suppression using antisense RNA strongly compromised the androgen-dependent proliferation of LNCaP cells (Chen et al. 2006). Overall, these findings suggest that c-Jun may be more involved in promoting AR function than in suppressing AR expression.
Sp1
Sp1 is a member of the Sp/KLF family of transcription factors that is involved in early development. Sp1 contains a zinc-finger protein motif, by which it binds directly to the consensus sequence 5′-(G/T)GGGCGG(G/A)(G/A)(C/T)-3′ (GC-box) and enhances gene transcription (Black et al. 2001).
In 1993, Faber et al. characterized the AR promoter region and identified a short GC-box (−59/−32 bp from TSS) and a long homopurine stretch (−117/−60 bp from TSS). They also implicated Sp1 in the control of AR transcription using a gene reporter assay and footprint analysis (Faber et al. 1993). These results were supported by a study demonstrating that the introduction of a mutation into the GC-box in the AR promoter region decreased AR transcription, as measured by CAT assay (Takane & McPhaul 1996). This finding was recently confirmed using LNCaP cells, showing that Sp1 overexpression increased AR transcription (Yuan et al. 2005). However, although a relationship between Sp1 and AR has been demonstrated, to the best of our knowledge, there have been no reports concerning the role of Sp1 in PCa.
p53
p53 is encoded by the TP53 gene, and is a tumor suppressor protein and transcription factor that binds to the p53-specific sequence (5′-(A/G)(A/G)(A/G)C(A/T)(T/A)G(T/C)(T/C)(T/C)-3′ (Matlashewski et al. 1984, Isobe et al. 1986, McBride et al. 1986, Kern et al. 1991). p53 is important in multicellular organisms, where it regulates the cell cycle, cellular apoptosis, and DNA repair, and functions as a tumor suppressor. As such, p53 has been described as ‘the guardian of the genome’, referring to its role in preventing genome mutation.
Forced p53 expression in LNCaP cells reduced AR transcription, while conversely, p53 knockdown increased AR transcription by binding to the p53 DNA-binding consensus sequence in the AR promoter region (−488/−469 bp from TSS; Alimirah et al. 2007).
Numerous studies concerning p53 have been performed in PCa and other solid cancers, and have suggested that mutations in the TP53 gene are associated with PCa progression (Navone et al. 1993, Bauer et al. 1995, Heidenberg et al. 1995, Nesslinger et al. 2003). Moreover, TP53 mutations may be an indicator of poor prognosis in PCa (Bauer et al. 1995, Heidenberg et al. 1995). Consistent with the above observations, it is interesting to note that the majority of metastatic PCa-derived cell lines harbor TP53 and/or AR mutations (Sobel & Sadar 2005). These observations suggest an important functional relationship between p53 and AR in the progression of PCa.
Foxo3a
Foxo3a belongs to the subclass ‘O’ of the forkhead family of transcription factors. These are characterized by a distinct forkhead DNA-binding domain, and bind to the Foxo-response element (5′-TTGTTTAC-3′) (Durham et al. 1999, Furuyama et al. 2000). There are three other human Foxo family members: Foxo1, Foxo4, and Foxo6. Foxo3a likely functions as a trigger for apoptosis through upregulation of pro-apoptotic proteins such as Bim and PUMA (Ekoff et al. 2007), or the downregulation of anti-apoptotic proteins such as FLIP (Skurk et al. 2004). Deregulation of Foxo3a is involved in tumorigenesis; for example, translocation of this gene with the MLL gene is associated with secondary acute leukemia (Myatt & Lam 2007), and Foxo3a is thus known as a tumor suppressor.
Chang and colleagues reported that Foxo3a positively regulated AR transcription by binding to the Foxo-response element in the AR promoter region (−1297/−1290 bp from TSS), and demonstrated a preventative role for the AR in the apoptosis of LNCaP cells by inhibition of the phosphoinositide 3-kinase/Akt signaling pathway (Yang et al. 2005).
The Foxo3a protein is the most highly expressed Foxo family member in PCa cells. It is hyperphosphorylated and markedly reduced in CRPC cells compared with androgen-dependent PCa cells (Lynch et al. 2005). Thus, Foxo function is compromised in CRPC cells, which appears to be incompatible with the observation that AR is frequently overexpressed in CRPC, but is consistent with its function in promoting apoptosis.
Lymphoid enhancer-binding factor 1
Lymphoid enhancer-binding factor 1 (LEF1) is the nuclear transducer of the activated-Wnt pathway. It binds to the LEF/TCF-binding site, 5′-(A/T)(A/T)CAAG-3′, and regulates the expression of its target genes (Roose & Clevers 1999). The Wnt-1/β-catenin/LEF1 pathway has been implicated in AR transcription, and Wnt-1 signaling leads to activation of the LEF1 complex and increased AR transcription (Yang et al. 2006). Moreover, LEF1 also positively regulates AR transcription by binding directly to LEF/TCF-binding sites (between −2000 and +0 bp from TSS), and was shown by microarray analysis to be upregulated in CRPC cells (Li et al. 2009).
Many studies have indicated a functional link between Wnt signaling and PCa (Yardy & Brewster 2005, Verras & Sun 2006), and intriguingly, a specific protein–protein interaction between β-catenin and AR resulting in AR transactivation has been demonstrated (Yang et al. 2002). Levels of both Wnt-1 and β-catenin were low in normal prostate cells, but were highly expressed in PCa cells. Increased Wnt-1 and β-catenin expression levels were also directly related to the Gleason score and to serum prostate-specific antigen (PSA) levels in PCa patients (Chen et al. 2004a,b). In addition, many studies have reported abnormal expression and mutation of β-catenin in PCa and in other solid cancers (Yardy & Brewster 2005). Synchronous activation of K-ras and β-catenin significantly reduced survival in a mouse model, associated with accelerated tumorigenesis and the development of invasive carcinoma (Pearson et al. 2009). In addition, Wnt/β-catenin activation promoted PCa progression in another mouse model (Yu et al. 2010), and the small molecule inhibitor of Wnt/β-catenin signaling, PKF118–310, has recently been shown to inhibit the proliferation of PCa cells (Lu et al. 2009).
Purine-rich element-binding protein α
Purine-rich element-binding protein α (PURα) is a nuclear protein with the ability to specifically bind to a purine-rich element found in single-stranded DNA (Bergemann & Johnson 1992, Bergemann et al. 1992). PURα binds to both DNA and RNA, and is believed to be involved in diverse functions, including DNA replication, gene transcription, mRNA translation, and RNA transport (Gallia et al. 2000). Several studies have indicated a role for PURα in the regulation of cell growth (Chang et al. 1996, Itoh et al. 1998, Stacey et al. 1999, Gallia et al. 2000, Barr & Johnson 2001, Darbinian et al. 2001, Lezon-Geyda et al. 2001).
Ferrari's group reported that AR transcription was inhibited by a novel transcriptional complex containing PURα and heterogeneous nuclear ribonucleoprotein-K (hnRNP-K), through binding to a specific sequence (repressor element) in the AR gene 5′-untranslated region. Furthermore, PURα expression was decreased in CRPC cells and tissues, implicating it in the pathogenesis of CRPC (Wang et al. 2008).
PURα expression is attenuated in CRPC cells compared with androgen-dependent PCa cells (Inoue et al. 2008). Recent studies demonstrated that overexpression of PURα in PC-3 and DU145 cells repressed their proliferation in vitro (Wang et al. 2008). Intriguingly, PURα has been shown to interact with several cellular regulatory proteins, including the E2F-1 and hypophosphorylated form of retinoblastoma protein (pRb; Johnson et al. 1995, Darbinian et al. 1999), both of which have been implicated in PCa progression (Yeh et al. 1998, Davis et al. 2006).
NFκB
NFκB (p65) is a protein complex that controls the transcription of various target genes, and is involved in cellular responses to stimuli such as stresses, cytokines, and infections (Gilmore 1999, 2006, Tian & Brasier 2003, Brasier 2006, Perkins 2007). NFκB regulates the expression of genes controlling cell proliferation and survival. Aberrant activation of NFκB is frequently seen in many cancers, and induces the expression of genes promoting cell proliferation and protecting against apoptosis. Conversely, defects in NFκB result in suppression of cell growth and increased susceptibility to apoptosis, leading to increased cell death. NFκB inhibition can suppress tumor growth, induce apoptosis, and sensitize cells to anti-cancer agents in various cancers.
NFκB was recently found to positively regulate AR transcription and cell growth in PCa cells (Zhang et al. 2009), though it was previously shown to act as a negative regulator of AR transcription in rat hepatic cells (Supakar et al. 1995). Furthermore, the inhibitor of NFκB has shown antitumor activity, even in CRPC cells. The results of another study using rat Sertoli cells support the positive regulation of AR expression by NFκB (Zhang et al. 2004).
Several studies have examined the expression of NFκB in PCa, and its relationship to clinical features. NFκB was overexpressed in prostatic intraepithelial neoplasia and PCa compared with benign epithelium (Sweeney et al. 2004), and recent studies found that NFκB expression was predictive of biochemical recurrence in patients with positive surgical margins after radical prostatectomy (Ismail et al. 2004). Nuclear localization of NFκB is increased in PCa with lymph node metastasis (Ismail et al. 2004), and can be used to predict patient outcome (Lessard et al. 2003). These results suggest that NFκB is frequently activated in PCa, and that its expression may be related to progression. NFκB is constitutively activated in CRPC xenografts where AR expression is also upregulated, suggesting a positive correlation between NFκB and AR expression (Chen & Sawyers 2002, Chen et al. 2004a,b).
Twist1
Twist1 belongs to the family of basic helix–loop–helix transcription factors that binds to the E-box sequence (5′-CANNTG-3′), and has been proposed to be an oncogene (Olson & Klein 1994, Maestro et al. 1999). Gene profiling analyses revealed that upregulation of Twist1 was associated with malignant transformation (van Doorn et al. 2004, Hoek et al. 2004). In addition, increased Twist1 expression has been detected in various malignant tumors compared with its expression in nonmalignant tissues (Maestro et al. 1999, Rosivatz et al. 2002), and was correlated with poorer outcome and shorter survival (Hoek et al. 2004). Recent evidence has also implicated Twist1 as a key factor responsible for metastasis (Yang et al. 2004).
We recently showed that Twist positively regulated AR expression in response to oxidative stress induced by androgen deprivation (Shiota et al. 2010). This finding is also supported by the study, similar to Myc (Takane & McPhaul 1996). Twist1 is a well-known master regulator of EMT, which may indicate a functional link between EMT and androgen/AR signaling.
Twist1 was upregulated in PCa with high Gleason score, and was involved in its colony forming and invasive abilities (Kwok et al. 2005). In another report, nuclear Twist expression was an important predictive factor for the metastatic potential of primary PCa (Yuen et al. 2007).
E2F/Rb
The E2F family of transcription factors consists of nine members, all of which bind to the E2F-binding site (5′-TTTCGCGC-3′) in the target promoter sequence. Three of them are activators: E2F-1, E2F-2, and E2F-3a, while the remaining six, E2F-3b and E2F-4–8, act as suppressors. The tumor suppressor protein pRb binds to E2F-1, and thus prevents its transcription-promoting activity. In the absence of pRb, E2F-1 transactivates its target genes, which facilitate the G1/S transition phase and S-phase (Pardee et al. 2004).
E2F-1 was shown to negatively regulate AR transcription in LNCaP cells (Davis et al. 2006). In this study, E2F-1 expression was elevated during prostate carcinogenesis and PCa progression, while AR expression was decreased in metastatic tissues from CRPC, in contrast to the results of many previous studies. Paradoxically, Knudsen's group recently reported that pRb knockdown with E2F-1 and E2F-3a overexpression cooperatively upregulated AR transcription in LNCaP cells (Sharma et al. 2010). In clinical samples, pRb and E2F-1 expression were negatively and positively correlated with AR expression, respectively. Furthermore, pRb expression in clinical samples was inversely correlated with the transition to CRPC.
Rb mutations have been linked to the development of PCa, and loss of heterozygosity of the Rb locus has been observed in clinical PCa samples (Ittmann & Wieczorek 1996). In a mouse model, pRb inactivation promoted prostate carcinogenesis and PCa progression (Maddison et al. 2004, Zhou et al. 2006). Intriguingly, fluorescence in situ hybridization analysis revealed that loss of the Rb gene was nearly four times more common after ADT than before therapy (22 vs 6%; Kaltz-Wittmer et al. 2000).
Sterol regulatory element-binding protein-1
Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element (5′-TCACNCCAC-3′). Mammalian SREBPs consist of SREBP-1 and SREBP-2, encoded by SREBF-1 and SREBF-2, respectively. SREBPs belong to the basic helix–loop–helix leucine zipper class of transcription factors (Yokoyama et al. 1993). Inactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. Decreased levels of sterols are associated with cleavage of SREBPs and translocation of the N-terminal domain to the nucleus. These activated SREBPs then bind to a specific sterol regulatory element, thus upregulating the synthesis of enzymes involved in sterol biosynthesis (Gasic 1994, Wang et al. 1994). Sterols in turn inhibit the cleavage of SREBPs, thus reducing the synthesis of additional sterols via negative feedback.
SREBP-1 was recently found to positively regulate AR transcription in LNCaP cells. SREBP-1 binding to the sterol regulatory element (−347/−336 bp from TSS) was demonstrated by gel-shift assay and chromatin-immunoprecipitation assay, while the regulation of AR transcription by SREBP-1 was proven by gene reporter assay using the AR promoter region (Huang et al. 2010).
SREBPs and their downstream effector genes have been found to be upregulated during progression to CRPC in the LNCaP xenograft model, as well as in clinical specimens of PCa (Ettinger et al. 2004). Intriguingly, 5-α reductase type 2 was also regulated by SREBPs in mouse prostate (Seo et al. 2009), and androgens and AR were found to reciprocally mediate SREBP-1 expression in PCa cells (Heemers et al. 2006, Ngan et al. 2009). This mutual regulation of SREBPs and androgen/AR signaling suggests a relationship between lipogenesis and PCa. In addition, pharmacologic inhibition of lipogenesis or RNA interference-mediated downregulation of key lipogenic genes induced apoptosis in cancer cell lines and reduced tumor growth in xenograft models. Lipogenesis is already seen in the earliest stages of prostate carcinogenesis, and increases with the development of CRPC (Swinnen et al. 2004).
Other factors
In addition to the transcription factors themselves, other molecules related to extracellular and intracellular signal transduction have also been implicated in AR transcription, through their regulation of known or unknown transcription factors (Table 1). Several of these factors have been reported to be involved in prostate carcinogenesis and PCa progression.
Clinical implications of targeting AR expression in PCa
As noted above, AR expression is regulated at the transcriptional level by several transcription factors, and various transcription factors are upregulated in PCa and CRPC, implicating them in the pathogenesis of these conditions. Suppression of AR expression is known to induce tumor regression in PCa, and even in CRPC (Chen et al. 2004a,b), and a strategy targeting AR expression may therefore be applicable to the treatment of PCa and CRPC. Indeed, the suppression of factors regulating AR expression using various methods, including RNA interference-mediated knockdown, small molecules, and antibodies, suppressed cell growth. The agents affecting AR transcription are listed in Table 2. In this list, a few inconsistencies among the reports were found. First, in androgen and synthetic androgen, R1881 had suppressive effect on AR expression at transcriptional level whereas Lee et al. reported dihydrotestosterone upregulated AR transcriptional level. Secondly, various histone deacetylase (HDAC) inhibitors downregulated AR expression in LNCaP cells although only Kim et al. (2007) reported that sodium butyrate upregulated AR expression. Although these inconsistencies might be derived from the differences of experimental condition, our data supported the result that androgen including dihydrotestosterone suppressed AR transcript (data not shown). Thus, androgen suppressed AR transcript whereas androgen is known to increase AR protein level by enhancing stability of AR protein (Gregory et al. 2001). This fact indicates that androgen functions not only as a ligand of the AR, but also as an AR stabilizer. Thus, androgen coordinately activates genomic and non-genomic AR downstream signaling.
These agents listed in Table 2 can be classified into several categories, according to their functions, and their therapeutic potentials are discussed below.
HDAC inhibitors have been intensively investigated as AR suppressors. Various HDAC inhibitors suppressed AR expression in LNCaP cells, supposedly at the transcriptional level, consistent with the results of many studies showing that HDAC inhibitors inhibited cell growth in PCa, and that HDAC was closely implicated in PCa progression (Abbas & Gupta 2008). So far, several HDAC inhibitors have been shown to exert anticancer effects in PCa using in vitro and in vivo models (Butler et al. 2000, Kuefer et al. 2004, Rephaeli et al. 2005, Kulp et al. 2006, Shabbeer et al. 2007, Sargeant et al. 2008, Hwang et al. 2010). Recently, a phase II trial using a HDAC inhibitor romidepsin was conducted in chemo-naïve patients with progressing and metastatic CRPC. However, the result was rather disappointing (Molife et al. 2010). Similarly, a phase II trial using another HDAC inhibitor vorinostat in advanced PCa patients progressing on prior chemotherapy showed an unsatisfactory result (Bradley et al. 2009). Also, the HDAC inhibitor, panobinostat, in CRPC patients exerted no remarkable efficiency in a phase I trial (Rathkopf et al. 2010). Thus, HDAC inhibitors seem to be less promising, at least in the treatment of CRPC.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been available for many years and are widely used throughout the world. NSAIDs have also been proved to suppress AR transcription through modulation of transcription factors responsible for AR expression. Several preclinical studies have shown that NSAIDs inhibited PCa proliferation and induced cellular apoptosis in vitro and in vivo (Goluboff et al. 1999, Lim et al. 2003, Patel et al. 2005, Shigemura et al. 2005). Furthermore, several clinical trials have proven the efficiency of NSAIDs for the treatment of PCa. In a pilot study, the COX-2 inhibitor, celecoxib, reduced the rate of elevation of PSA after biochemical recurrence following radical prostatectomy and radiation therapy (Pruthi et al. 2004). This finding was proven by the following phase II trial (Pruthi et al. 2006). Similarly, sulindac sulfone (exisulind), a metabolite of the NSAID sulindac, also exerted a favorable effect on PSA recurrence after radical prostatectomy (Goluboff et al. 2001).
Selenium-containing compounds have also been extensively examined and have been found to suppress AR expression, probably at the transcriptional level. In vitro studies using androgen-dependent LNCaP and androgen-independent PC-3 cells have revealed that selenium could inhibit cell proliferation and induce apoptosis (Dong et al. 2003, Zhao et al. 2004). Also, in in vivo studies, selenium suppressed AR expression and growth of human PCa xenografts (Lee et al. 2006, Bhattacharyya et al. 2008). These findings are compatible with the results of a large-scale trial (Nutritional Prevention of Cancer (NPC) Trial; the Selenium and Vitamin E Chemoprevention Trial, SELECT), which indicated that selenium supplementation could reduce prostate carcinogenesis (Duffield-Lillico et al. 2003, Lippman et al. 2005). Because inorganic selenium compounds are known to produce genotoxic effects, organic selenium-containing compounds, which are better tolerated and exhibit anti-carcinogenic activity, seem to be more suitable for clinical usage.
Natural compounds, including polyphenols and natural resins, have also been investigated and found to reduce AR expression at both the transcriptional and post-transcriptional levels, with supposed tumor-suppressor roles in PCa. Many preclinical studies showed that various natural compounds exerted suppressive effects on PCa growth in vitro and in vivo. In addition, a phase II trial was conducted using phytochemicals in pomegranate juice for patients with recurrence after surgery or radiation for PCa, which showed that the PSA elevation rate was mitigated (Pantuck et al. 2006). Moreover, several chemicals that inhibit signaling pathways have also been reported, and show similar results to direct inhibition of their target molecules.
These and other agents under development that target AR expression have potential as chemopreventive compounds and therapeutic agents for PCa. Targeting AR expression at the transcriptional level, rather than directly targeting the AR itself through the use, e.g., of anti-androgens has several advantages. First, compounds targeting AR expression may exert additional effects on other targets implicated in tumor progression and suppression; indeed, some of the agents listed in Table 2 could affect the expression of various genes, such as cyclins and E2F, and signaling pathways, such as the Akt and mitogen-activated protein kinase pathways. Secondly, this strategy may be applicable to AR splice variants that are potentially refractory to anti-androgens, which bind to the ligand-binding domain of the AR, because splice variants may lack the ligand-binding domain and are thus active in the absence of ligand binding.
Conclusions and future directions
AR is known to contribute to prostate tumorigenesis and progression, as well as to the development of CRPC. This is supported by substantial evidence implicating the aberrant expression or improper regulation of AR in these disorders. Several factors, including transcription factors, regulate AR expression, and offer a feasible strategy for developing new therapeutic agents to treat both androgen-dependent PCa and CRPC. Recent research into AR splice variants has revealed the importance of developing AR-expression-targeting therapeutics able to regulate the expression of AR splice variants.
Further in vitro and in vivo studies, together with intelligently designed clinical trials, are needed to evaluate compounds suppressing AR expression for treatment of PCa and CRPC. Moreover, based on the findings obtained so far, novel therapeutic strategies and agents for treatment of PCa and CRPC through disruption of AR expression should be developed.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by Health Sciences Research Grants for Clinical Research for Evidence Based Medicine and Grants-in-Aid for Cancer Research (016), from the Ministry of Health, Labour and Welfare, Japan; Kakenhi grants (22591769) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan; Research Promotion Grant from the Japanese Foundation for Prostate Research, Japan; and Grant-in-Aid for Cancer Research from the Fukuoka Foundation for Sound Health, Japan.
Acknowledgements
We apologize to authors whose works were inadvertently overlooked or could not be cited because of space constraints. We thank Edanz Group Japan for editorial assistance.
References
Abbas A & Gupta S 2008 The role of histone deacetylases in prostate cancer. Epigenetics 3 300–309.doi:10.4161/epi.3.6.7273.
Adam RM, Kim J, Lin J, Orsola A, Zhuang L, Rice DC & Freeman MR 2002 Heparin-binding epidermal growth factor-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function. Endocrinology 143 4599–4608.doi:10.1210/en.2002-220561.
Adhikary S & Eilers M 2005 Transcriptional regulation and transformation by Myc proteins. Nature Reviews. Molecular Cell Biology 6 635–645.doi:10.1038/nrm1703.
Alimirah F, Panchanathan R, Chen J, Zhang X, Ho SM & Choubey D 2007 Expression of androgen receptor is negatively regulated by p53. Neoplasia 9 1152–1159.doi:10.1593/neo.07769.
Ameyar M, Wisniewska M & Weitzman JB 2003 A role for AP-1 in apoptosis: the case for and against. Biochimie 85 747–752.doi:10.1016/j.biochi.2003.09.006.
Barr SM & Johnson EM 2001 Ras-induced colony formation and anchorage-independent growth inhibited by elevated expression of Purα in NIH3T3 cells. Journal of Cellular Biochemistry 81 621–638.doi:10.1002/jcb.1099.
Bauer JJ, Sesterhenn IA, Mostofi KF, McLeod DG, Srivastava S & Moul JW 1995 p53 nuclear protein expression is an independent prognostic marker in clinically localized prostate cancer patients undergoing radical prostatectomy. Clinical Cancer Research 1 1295–1300.
Bergemann AD & Johnson EM 1992 The HeLa Pur factor binds single-stranded DNA at a specific element conserved in gene flanking regions and origins of DNA replication. Molecular and Cellular Biology 12 1257–1265.
Bergemann AD, Ma ZW & Johnson EM 1992 Sequence of cDNA comprising the human pur gene and sequence-specific single-stranded-DNA-binding properties of the encoded protein. Molecular and Cellular Biology 12 5673–5682.
Bhattacharyya RS, Krishnan AV, Swami S & Feldman D 2006 Fulvestrant (ICI 182,780) down-regulates androgen receptor expression and diminishes androgenic responses in LNCaP human prostate cancer cells. Molecular Cancer Therapeutics 5 1539–1549.doi:10.1158/1535-7163.MCT-06-0065.
Bhattacharyya RS, Husbeck B, Feldman D & Knox SJ 2008 Selenite treatment inhibits LAPC-4 tumor growth and prostate-specific antigen secretion in a xenograft model of human prostate cancer. International Journal of Radiation Oncology, Biology, Physics 72 935–940.doi:10.1016/j.ijrobp.2008.07.005.
Black AR, Black JD & Azizkhan-Clifford J 2001 Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer. Journal of Cellular Physiology 188 143–160.doi:10.1002/jcp.1111.
Boxer LM & Dang CV 2001 Translocations involving c-myc and c-myc function. Oncogene 20 5595–5610.doi:10.1038/sj.onc.1204595.
Bradley D, Rathkopf D, Dunn R, Stadler WM, Liu G, Smith DC, Pili R, Zwiebel J, Scher H & Hussain M 2009 Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: a study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium. Cancer 115 5541–5549.doi:10.1002/cncr.24597.
Brasier AR 2006 The NF-κB regulatory network. Cardiovascular Toxicology 6 111–130.doi:10.1385/CT:6:2:111.
Brinkmann AO, Faber PW, van Rooij HC, Kuiper GG, Ris C, Klaassen P, van der Korput JA, Voorhorst MM, van Laar JH & Mulder E et al. 1989 The human androgen receptor: domain structure, genomic organization and regulation of expression. Journal of Steroid Biochemistry 34 307–310.doi:10.1016/0022-4731(89)90098-8.
Bubulya A, Zhou XF, Shen XQ, Fisher CJ & Shemshedini L 2000 c-Jun targets amino terminus of androgen receptor in regulating androgen-responsive transcription. Endocrine 13 55–62.doi:10.1385/ENDO:13:1:55.
Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA & Richon VM 2000 Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Research 60 5165–5170.
Chang CF, Gallia GL, Muralidharan V, Chen NN, Zoltick P, Johnson E & Khalili K 1996 Evidence that replication of human neurotropic JC virus DNA in glial cells is regulated by the sequence-specific single-stranded DNA-binding protein Purα. Journal of Virology 70 4150–4156.
Chen CD & Sawyers CL 2002 NF-κB activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. Molecular and Cellular Biology 22 2862–2870.doi:10.1128/MCB.22.8.2862-2870.2002.
Chen S, Ruan Q, Bedner E, Deptala A, Wang X, Hsieh TC, Traganos F & Darzynkiewicz Z 2001 Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines. Cell Proliferation 34 293–304.doi:10.1046/j.0960-7722.2001.00213.x.
Chen G, Shukeir N, Potti A, Sircar K, Aprikian A, Goltzman D & Rabbani SA 2004a Up-regulation of Wnt-1 and β-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer 101 1345–1356.doi:10.1002/cncr.20518.
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG & Sawyers CL 2004b Molecular determinants of resistance to antiandrogen therapy. Nature Medicine 10 33–39.doi:10.1038/nm972.
Chen SY, Cai C, Fisher CJ, Zheng Z, Omwancha J, Hsieh CL & Shemshedini L 2006 c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation. Oncogene 25 7212–7223.doi:10.1038/sj.onc.1209705.
Chen D, Cui QC, Yang H, Barrea RA, Sarkar FH, Sheng S, Yan B, Reddy GP & Dou QP 2007 Clioquinol, a therapeutic agent for Alzheimer's disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts. Cancer Research 67 1636–1644.doi:10.1158/0008-5472.CAN-06-3546.
Chen H, Liu W, Roberts W, Hooker S, Fedor H, DeMarzo A, Isaacs W & Kittles RA 2010 8q24 allelic imbalance and MYC gene copy number in primary prostate cancer. Prostate Cancer and Prostatic Diseases 13 238–243.doi:10.1038/pcan.2010.20.
Chintharlapalli S, Papineni S & Safe S 2007 1,1-bis(3′-indolyl)-1-(p-substitutedphenyl)methanes inhibit growth, induce apoptosis, and decrease the androgen receptor in LNCaP prostate cancer cells through peroxisome proliferator-activated receptor gamma-independent pathways. Molecular Pharmacology 71 558–569.doi:10.1124/mol.106.028696.
Chiu FL & Lin JK 2008 Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and xenografts. Prostate 68 61–71.doi:10.1002/pros.20690.
Chun JY, Nadiminty N, Lee SO, Onate SA, Lou W & Gao AC 2006 Mechanisms of selenium down-regulation of androgen receptor signaling in prostate cancer. Molecular Cancer Therapeutics 5 913–918.doi:10.1158/1535-7163.MCT-05-0389.
Darbinian N, Gallia GL, Kundu M, Shcherbik N, Tretiakova A, Giordano A & Khalili K 1999 Association of Purα and E2F-1 suppresses transcriptional activity of E2F-1. Oncogene 18 6398–6402.doi:10.1038/sj.onc.1203011.
Darbinian N, Gallia GL, King J, Del Valle L, Johnson EM & Khalili K 2001 Growth inhibition of glioblastoma cells by human Purα. Journal of Cellular Physiology 189 334–340.doi:10.1002/jcp.10029.
Davis JN, Wojno KJ, Daignault S, Hofer MD, Kuefer R, Rubin MA & Day M 2006 Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer. Cancer Research 66 11897–11906.doi:10.1158/0008-5472.CAN-06-2497.
Debes JD & Tindall DJ 2004 Mechanisms of androgen-refractory prostate cancer. New England Journal of Medicine 351 1488–1490.doi:10.1056/NEJMp048178.
Dehm SM, Schmidt LJ, Heemers HV, Vessella RL & Tindall DJ 2008 Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Research 68 5469–5477.doi:10.1158/0008-5472.CAN-08-0594.
Deng X, Liu H, Huang J, Cheng L, Keller ET, Parsons SJ & Hu CD 2008 Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression. Cancer Research 68 9663–9670.doi:10.1158/0008-5472.CAN-08-2229.
Ding Y, Yuan HQ, Kong F, Hu XY, Ren K, Cai J, Wang XL & Young CY 2007 Ectopic expression of neurotrophic peptide derived from saposin C increases proliferation and upregulates androgen receptor expression and transcriptional activity in human prostate cancer cells. Asian Journal of Andrology 9 601–609.doi:10.1111/j.1745-7262.2007.00328.x.
Dong Y, Zhang H, Hawthorn L, Ganther HE & Ip C 2003 Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array. Cancer Research 63 52–59.
van Doorn R, Dijkman R, Vermeer MH, Out-Luiting JJ, van der Raaij-Helmer EM, Willemze R & Tensen CP 2004 Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sezary syndrome identified by gene expression analysis. Cancer Research 64 5578–5586.doi:10.1158/0008-5472.CAN-04-1253.
Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs ET, Marshall JR, Clark LC & Nutritional Prevention of Cancer Study Group 2003 Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU International 91 608–612.doi:10.1046/j.1464-410X.2003.04167.x.
Durham SK, Suwanichkul A, Scheimann AO, Yee D, Jackson JG, Barr FG & Powell DR 1999 FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. Endocrinology 140 3140–3146.doi:10.1210/en.140.7.3140.
Edwards J, Krishna NS, Mukherjee R & Bartlett JM 2004 The role of c-Jun and c-Fos expression in androgen-independent prostate cancer. Journal of Pathology 204 153–158.doi:10.1002/path.1605.
Ekoff M, Kaufmann T, Engström M, Motoyama N, Villunger A, Jönsson JI, Strasser A & Nilsson G 2007 The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells. Blood 110 3209–3217.doi:10.1182/blood-2007-02-073957.
Emami KH, Brown LG, Pitts TE, Sun X, Vessella RL & Corey E 2009 Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. Prostate 69 1481–1492.doi:10.1002/pros.20998.
Ettinger SL, Sobel R, Whitmore TG, Akbari M, Bradley DR, Gleave ME & Nelson CC 2004 Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence. Cancer Research 64 2212–2221.doi:10.1158/0008-5472.CAN-2148-2.
Faber PW, van Rooij HC, van der Korput HA, Baarends WM, Brinkmann AO, Grootegoed JA & Trapman J 1991 Characterization of the human androgen receptor transcription unit. Journal of Biological Chemistry 266 10743–10749.
Faber PW, van Rooij HC, Schipper HJ, Brinkmann AO & Trapman J 1993 Two different, overlapping pathways of transcription initiation are active on the TATA-less human androgen receptor promoter. The role of Sp1. Journal of Biological Chemistry 268 9296–9301.
Furuyama T, Nakazawa T, Nakano I & Mori N 2000 Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochemical Journal 349 629–634.doi:10.1042/0264-6021:3490629.
Gallia GL, Johnson EM & Khalili K 2000 Purα: a multifunctional single-stranded DNA- and RNA-binding protein. Nucleic Acids Research 28 3197–3205.doi:10.1093/nar/28.17.3197.
Gasic GP 1994 Basic-helix–loop–helix transcription factor and sterol sensor in a single membrane-bound molecule. Cell 77 17–19.doi:10.1016/0092-8674(94)90230-5.
Gilmore TD 1999 The Rel/NF-κB signal transduction pathway: introduction. Oncogene 18 6842–6844.doi:10.1038/sj.onc.1203237.
Gilmore TD 2006 Introduction to NF-κB: players, pathways, perspectives. Oncogene 25 6680–6684.doi:10.1038/sj.onc.1209954.
Goluboff ET, Shabsigh A, Saidi JA, Weinstein IB, Mitra N, Heitjan D, Piazza GA, Pamukcu R, Buttyan R & Olsson CA 1999 Exisulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis. Urology 53 440–445.doi:10.1016/S0090-4295(98)00513-5.
Goluboff ET, Prager D, Rukstalis D, Giantonio B, Madorsky M, Barken I, Weinstein IB, Partin AW, Olsson CA & UCLA Oncology Research Network 2001 Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. Journal of Urology 166 882–886.doi:10.1016/S0022-5347(05)65856-9.
Gong Y, Blok LJ, Perry JE, Lindzey JK & Tindall DJ 1995 Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP. Endocrinology 136 2172–2178.doi:10.1210/en.136.5.2172.
Grad JM, Dai JL, Wu S & Burnstein KL 1999 Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding region are involved in androgen-mediated up-regulation of AR messenger RNA. Molecular Endocrinology 13 1896–1911.doi:10.1210/me.13.11.1896.
Gregory CW, Hamil KG, Kim D, Hall SH, Pretlow TG, Mohler JL & French FS 1998 Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. Cancer Research 58 5718–5724.
Gregory CW, Johnson RT Jr, Mohler JL, French FS & Wilson EM 2001 Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Research 61 2892–2898.
Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J & Tepper CG et al. 2009 A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Research 69 2305–2313.doi:10.1158/0008-5472.CAN-08-3795.
Hawksworth D, Ravindranath L, Chen Y, Furusato B, Sesterhenn IA, McLeod DG, Srivastava S & Petrovics G 2010 Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence. Prostate Cancer and Prostatic Diseases 13 311–315.doi:10.1038/pcan.2010.31.
He ML, Yuan HQ, Jiang AL, Gong AY, Chen WW, Zhang PJ, Young CY & Zhang JY 2006 Gum mastic inhibits the expression and function of the androgen receptor in prostate cancer cells. Cancer 106 2547–2555.doi:10.1002/cncr.21935.
Heemers HV, Verhoeven G & Swinnen JV 2006 Androgen activation of the sterol regulatory element-binding protein pathway: current insights. Molecular Endocrinology 20 2265–2277.doi:10.1210/me.2005-0479.
Heidenberg HB, Sesterhenn IA, Gaddipati JP, Weghorst CM, Buzard GS, Moul JW & Srivastava S 1995 Alteration of the tumor suppressor gene p53 in a high fraction of hormone refractory prostate cancer. Journal of Urology 154 414–421.doi:10.1016/S0022-5347(01)67065-4.
Hermeking H 2003 The MYC oncogene as a cancer drug target. Current Cancer Drug Targets 3 163–175.doi:10.2174/1568009033481949.
Hess J, Angel P & Schorpp-Kistner M 2004 AP-1 subunits: quarrel and harmony among siblings. Journal of Cell Science 117 5965–5973.doi:10.1242/jcs.01589.
Hoek K, Rimm DL, Williams KR, Zhao H, Ariyan S, Lin A, Kluger HM, Berger AJ, Cheng E & Trombetta ES et al. 2004 Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Research 64 5270–5282.doi:10.1158/0008-5472.CAN-04-0731.
Hoshino K, Ishiguro H, Teranishi JI, Yoshida SI, Umemura S, Kubota Y & Uemura H 2010 Regulation of androgen receptor expression through angiotensin II type 1 receptor in prostate cancer cells. Prostate 71 964–975.doi:10.1002/pros.21312.
Hsu JC, Zhang J, Dev A, Wing A, Bjeldanes LF & Firestone GL 2005 Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells. Carcinogenesis 26 1896–1904.doi:10.1093/carcin/bgi155.
Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL & Isaacs WB et al. 2009 Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Research 69 16–22.doi:10.1158/0008-5472.CAN-08-2764.
Huang WC, Havel JJ, Zhau HE, Qian WP, Lue HW, Chu CY, Nomura T & Chung LW 2008 β2-Microglobulin signaling blockade inhibited androgen receptor axis and caused apoptosis in human prostate cancer cells. Clinical Cancer Research 14 5341–5347.doi:10.1158/1078-0432.CCR-08-0793.
Huang PH, Wang D, Chuang HC, Wei S, Kulp SK & Chen CS 2009 α-Tocopheryl succinate and derivatives mediate the transcriptional repression of androgen receptor in prostate cancer cells by targeting the PP2A-JNK-Sp1-signaling axis. Carcinogenesis 30 1125–1131.doi:10.1093/carcin/bgp112.
Huang WC, Zhau HE & Chung LW 2010 Androgen receptor survival signaling is blocked by anti-β2-microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells. Journal of Biological Chemistry 285 7947–7956.doi:10.1074/jbc.M109.092759.
Husbeck B, Bhattacharyya RS, Feldman D & Knox SJ 2006 Inhibition of androgen receptor signaling by selenite and methylseleninic acid in prostate cancer cells: two distinct mechanisms of action. Molecular Cancer Therapeutics 5 2078–2085.doi:10.1158/1535-7163.MCT-06-0056.
Hwang JJ, Kim YS, Kim MJ, Kim DE, Jeong IG & Kim CS 2010 Histone deacetylase inhibitor potentiates anticancer effect of docetaxel via modulation of Bcl-2 family proteins and tubulin in hormone refractory prostate cancer cells. Journal of Urology 184 2557–2564.doi:10.1016/j.juro.2010.07.035.
Inoue T, Leman ES, Yeater DB & Getzenberg RH 2008 The potential role of purine-rich element binding protein (PUR) α as a novel treatment target for hormone-refractory prostate cancer. Prostate 68 1048–1056.doi:10.1002/pros.20764.
Ismail HA, Lessard L, Mes-Masson AM & Saad F 2004 Expression of NfκB in prostate cancer lymph node metastases. Prostate 58 308–313.doi:10.1002/pros.10335.
Isobe M, Emanuel BS, Givol D, Oren M & Croce CM 1986 Localization of gene for human p53 tumour antigen to band 17p13. Nature 320 84–85.doi:10.1038/320084a0.
Itoh H, Wortman MJ, Kanovsky M, Uson RR, Gordon RE, Alfano N & Johnson EM 1998 Alterations in Purα levels and intracellular localization in the CV-1 cell cycle. Cell Growth and Differentiation 9 651–665.
Ittmann MM & Wieczorek R 1996 Alterations of the retinoblastoma gene in clinically localized, stage B prostate adenocarcinomas. Human Pathology 27 28–34.doi:10.1016/S0046-8177(96)90134-3.
Iwata T, Schultz D, Hicks J, Hubbard GK, Mutton LN, Lotan TL, Bethel C, Lotz MT, Yegnasubramanian S & Nelson WG et al. 2010 MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells. PLoS ONE 5 e9427 doi:10.1371/journal.pone.0009427.
Jackson KM, Frazier MC & Harris WB 2007 Suppression of androgen receptor expression by dibenzoylmethane as a therapeutic objective in advanced prostate cancer. Anticancer Research 27 1483–1488.
Johnson EM, Chen PL, Krachmarov CP, Barr SM, Kanovsky M, Ma ZW & Lee WH 1995 Association of human Purα with the retinoblastoma protein, Rb, regulates binding to the single-stranded DNA Purα recognition element. Journal of Biological Chemistry 270 24352–24360.doi:10.1074/jbc.270.41.24352.
Kaltz-Wittmer C, Klenk U, Glaessgen A, Aust DE, Diebold J, Löhrs U & Baretton GB 2000 FISH analysis of gene aberrations (MYC, CCND1, ERBB2, RB, and AR) in advanced prostatic carcinomas before and after androgen deprivation therapy. Laboratory Investigation 80 1455–1464.
Kang HY, Huang HY, Hsieh CY, Li CF, Shyr CR, Tsai MY, Chang C, Chuang YC & Huang KE 2009 Activin A enhances prostate cancer cell migration through activation of androgen receptor and is overexpressed in metastatic prostate cancer. Journal of Bone and Mineral Research 24 1180–1193.doi:10.1359/jbmr.090219.
Kaseb AO, Chinnakannu K, Chen D, Sivanandam A, Tejwani S, Menon M, Dou QP & Reddy GP 2007 Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Research 67 7782–7788.doi:10.1158/0008-5472.CAN-07-1483.
Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C & Vogelstein B 1991 Identification of p53 as a sequence-specific DNA-binding protein. Science 252 1708–1711.doi:10.1126/science.2047879.
Kim J, Park H, Im JY, Choi WS & Kim HS 2007 Sodium butyrate regulates androgen receptor expression and cell cycle arrest in human prostate cancer cells. Anticancer Research 27 3285–3292.
Kuefer R, Hofer MD, Altug V, Zorn C, Genze F, Kunzi-Rapp K, Hautmann RE & Gschwend JE 2004 Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer. British Journal of Cancer 90 535–541.doi:10.1038/sj.bjc.6601510.
Kulp SK, Chen CS, Wang DS, Chen CY & Chen CS 2006 Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clinical Cancer Research 12 5199–5206.doi:10.1158/1078-0432.CCR-06-0429.
Kwok WK, Ling MT, Lee TW, Lau TC, Zhou C, Zhang X, Chua CW, Chan KW, Chan FL & Glackin C et al. 2005 Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Research 65 5153–5162.doi:10.1158/0008-5472.CAN-04-3785.
Lee HH, Ho CT & Lin JK 2004 Theaflavin-3,3′-digallate and penta-O-galloyl-β-d-glucose inhibit rat liver microsomal 5α-reductase activity and the expression of androgen receptor in LNCaP prostate cancer cells. Carcinogenesis 25 1109–1118.doi:10.1093/carcin/bgh106.
Lee SO, Yeon Chun J, Nadiminty N, Trump DL, Ip C, Dong Y & Gao AC 2006 Monomethylated selenium inhibits growth of LNCaP human prostate cancer xenograft accompanied by a decrease in the expression of androgen receptor and prostate-specific antigen (PSA). Prostate 66 1070–1075.doi:10.1002/pros.20329.
Lee JG, Zheng R, McCafferty-Cepero JM, Burnstein KL, Nanus DM & Shen R 2009 Endothelin-1 enhances the expression of the androgen receptor via activation of the c-myc pathway in prostate cancer cells. Molecular Carcinogenesis 48 141–149.doi:10.1002/mc.20462.
Lessard L, Mes-Masson AM, Lamarre L, Wall L, Lattouf JB & Saad F 2003 NF-κB nuclear localization and its prognostic significance in prostate cancer. BJU International 91 417–420.doi:10.1046/j.1464-410X.2003.04104.x.
Lezon-Geyda K, Najfeld V & Johnson EM 2001 Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia. Leukemia 15 954–962.doi:10.1038/sj.leu.2402108.
Li R, Wheeler T, Dai H, Frolov A, Thompson T & Ayala G 2004 High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate: cancer patients treated with radical prostatectomy. American Journal of Surgical Pathology 28 928–934.doi:10.1097/00000478-200407000-00013.
Li Y, Wang L, Zhang M, Melamed J, Liu X, Reiter R, Wei J, Peng Y, Zou X & Pellicer A et al. 2009 LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth, and invasion. Cancer Research 69 3332–3338.doi:10.1158/0008-5472.CAN-08-3380.
Lim JT, Piazza GA, Pamukcu R, Thompson WJ & Weinstein IB 2003 Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells. Clinical Cancer Research 9 4972–4982.
Linja MJ, Savinainen KJ, Saramäki OR, Tammela TL, Vessella RL & Visakorpi T 2001 Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Research 61 3550–3555.
Lippman SM, Goodman PJ, Klein EA, Parnes HL, Thompson IM Jr, Kristal AR, Santella RM, Probstfield JL, Moinpour CM & Albanes D et al. 2005 Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Journal of the National Cancer Institute 97 94–102.doi:10.1093/jnci/dji009.
Litvinov IV, De Marzo AM & Isaacs JT 2003 Is the Achilles' heel for prostate cancer therapy a gain of function in androgen receptor signaling? Journal of Clinical Endocrinology and Metabolism 88 2972–2982.doi:10.1210/jc.2002-022038.
Liu S & Yamauchi H 2010 Etoposide induces growth arrest and disrupts androgen receptor signaling in prostate cancer cells. Oncology Reports 23 165–170.doi:10.3892/or_00000730.
Loiarro M, Campo S, Arseni B, Rossi S, D'Alessio V, De Santis R, Sette C & Ruggiero V 2011 Anti-proliferative effect of a triazole derivative (ST1959) on LNCaP human prostate cancer cells through down-regulation of cyclin and androgen receptor expression. Prostate 71 32–41.doi:10.1002/pros.21219.
Lu W, Tinsley HN, Keeton A, Qu Z, Piazza GA & Li Y 2009 Suppression of Wnt/β-catenin signaling inhibits prostate cancer cell proliferation. European Journal of Pharmacology 602 8–14.doi:10.1016/j.ejphar.2008.10.053.
Lynch RL, Konicek BW, McNulty AM, Hanna KR, Lewis JE, Neubauer BL & Graff JR 2005 The progression of LNCaP human prostate cancer cells to androgen independence involves decreased FOXO3a expression and reduced p27KIP1 promoter transactivation. Molecular Cancer Research 3 163–169.doi:10.1158/1541-7786.MCR-04-0163.
Maddison LA, Sutherland BW, Barrios RJ & Greenberg NM 2004 Conditional deletion of Rb causes early stage prostate cancer. Cancer Research 64 6018–6025.doi:10.1158/0008-5472.CAN-03-2509.
Maestro R, Dei Tos AP, Hamamori Y, Krasnokutsky S, Sartorelli V, Kedes L, Doglioni C, Beach DH & Hannon GJ 1999 Twist is a potential oncogene that inhibits apoptosis. Genes and Development 13 2207–2217.doi:10.1101/gad.13.17.2207.
Marrocco DL, Tilley WD, Bianco-Miotto T, Evdokiou A, Scher HI, Rifkind RA, Marks PA, Richon VM & Butler LM 2007 Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation. Molecular Cancer Therapeutics 6 51–60.doi:10.1158/1535-7163.MCT-06-0144.
Mashima T, Okabe S & Seimiya H 2010 Pharmacological targeting of constitutively active truncated androgen receptor by nigericin and suppression of hormone-refractory prostate cancer cell growth. Molecular Pharmacology 78 846–854.doi:10.1124/mol.110.064790.
Matlashewski G, Lamb P, Pim D, Peacock J, Crawford L & Benchimol S 1984 Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO Journal 3 3257–3262.
McBride OW, Merry D & Givol D 1986 The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). PNAS 83 130–134.doi:10.1073/pnas.83.1.130.
Mitchell SH, Zhu W & Young CY 1999 Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Research 59 5892–5895.
Miyamoto H, Messing EM & Chang C 2004 Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate 61 332–353.doi:10.1002/pros.20115.
Mizokami A, Yeh SY & Chang C 1994 Identification of 3′,5′-cyclic adenosine monophosphate response element and other cis-acting elements in the human androgen receptor gene promoter. Molecular Endocrinology 8 77–88.doi:10.1210/me.8.1.77.
Molife LR, Attard G, Fong PC, Karavasilis V, Reid AH, Patterson S, Riggs CE Jr, Higano C, Stadler WM & McCulloch W et al. 2010 Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Annals of Oncology 21 109–113.doi:10.1093/annonc/mdp270.
Myatt SS & Lam EW 2007 The emerging roles of forkhead box (Fox) proteins in cancer. Nature Reviews. Cancer 7 847–859.doi:10.1038/nrc2223.
Navone NM, Troncoso P, Pisters LL, Goodrow TL, Palmer JL, Nicholas WW, von Eschenbach AC & Conti CJ 1993 p53 protein accumulation and gene mutation in the progression of human prostate carcinoma. Journal of the National Cancer Institute 85 1657–1669.doi:10.1093/jnci/85.20.1657.
Nesslinger NJ, Shi XB & deVere White RW 2003 Androgen-independent growth of LNCaP prostate cancer cells is mediated by gain-of-function mutant p53. Cancer Research 63 2228–2233.
Ngan S, Stronach EA, Photiou A, Waxman J, Ali S & Buluwela L 2009 Microarray coupled to quantitative RT-PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells. Oncogene 28 2051–2063.doi:10.1038/onc.2009.68.
Nicole DF, Karam E, Yuan-Wan S, John TP & Raghu S 2010 1,4-Phenylenebis(methylene)selenocyanate, but not selenomethionine, inhibits androgen receptor and Akt signaling in human prostate cancer cells. Cancer Prevention Research 3 975–984.doi:10.1158/1940-6207.CAPR-10-0054.
Olson EN & Klein WH 1994 bHLH factors in muscle development: dead lines and commitments, what to leave in and what to leave out. Genes and Development 8 1–8.doi:10.1101/gad.8.1.1.
Pan Y, Zhang JS, Gazi MH & Young CY 2003 The cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs celecoxib and nimesulide inhibit androgen receptor activity via induction of c-Jun in prostate cancer cells. Cancer Epidemiology, Biomarkers and Prevention 12 769–774.
Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong J, Barnard RJ, Seeram N, Liker H, Wang H & Elashoff R et al. 2006 Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clinical Cancer Research 12 4018–4026.doi:10.1158/1078-0432.CCR-05-2290.
Pardee AB, Li CJ & Reddy GP 2004 Regulation in S phase by E2F. Cell Cycle 3 1091–1094.doi:10.4161/cc.3.9.1143.
Patel MI, Subbaramaiah K, Du B, Chang M, Yang P, Newman RA, Cordon-Cardo C, Thaler HT & Dannenberg AJ 2005 Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism. Clinical Cancer Research 11 1999–2007.doi:10.1158/1078-0432.CCR-04-1877.
Pearson HB, Phesse TJ & Clarke AR 2009 K-ras and Wnt signaling synergize to accelerate prostate tumorigenesis in the mouse. Cancer Research 69 94–101.doi:10.1158/0008-5472.CAN-08-2895.
Perkins ND 2007 Integrating cell-signalling pathways with NF-κB and IKK function. Nature Reviews. Molecular Cell Biology 8 49–62.doi:10.1038/nrm2083.
Pruthi RS, Derksen JE & Moore D 2004 A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy. BJU International 93 275–278.doi:10.1111/j.1464-410X.2004.04601.x.
Pruthi RS, Derksen JE, Moore D, Carson CC, Grigson G, Watkins C & Wallen E 2006 Phase II trial of celecoxib in prostate-specific antigen recurrent prostate cancer after definitive radiation therapy or radical prostatectomy. Clinical Cancer Research 12 2172–2177.doi:10.1158/1078-0432.CCR-05-2067.
Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM, Hu J, Dzik-Jurasz A, Yang W & Scher HI 2010 A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemotherapy and Pharmacology 66 181–189.doi:10.1007/s00280-010-1289-x.
Ravenna L, Gulino A, Lubrano C, Sciarra F, Di Silverio F, D'Eramo G, Vacca A, Felli MP, Maroder M & Frati L et al. 1995 Androgenic and antiandrogenic control on epidermal growth factor, epidermal growth factor receptor, and androgen receptor expression in human prostate cancer cell line LNCaP. Prostate 26 290–298.doi:10.1002/pros.2990260604.
Ren F, Zhang S, Mitchell SH, Butler R & Young CY 2000 Tea polyphenols down-regulate the expression of the androgen receptor in LNCaP prostate cancer cells. Oncogene 19 1924–1932.doi:10.1038/sj.onc.1203511.
Rephaeli A, Blank-Porat D, Tarasenko N, Entin-Meer M, Levovich I, Cutts SM, Phillips DR, Malik Z & Nudelman A 2005 In vivo and in vitro antitumor activity of butyroyloxymethyl-diethyl phosphate (AN-7), a histone deacetylase inhibitor, in human prostate cancer. International Journal of Cancer 116 226–235.doi:10.1002/ijc.21030.
Rokhlin OW, Glover RB, Guseva NV, Taghiyev AF, Kohlgraf KG & Cohen MB 2006 Mechanisms of cell death induced by histone deacetylase inhibitors in androgen receptor-positive prostate cancer cells. Molecular Cancer Research 4 113–123.doi:10.1158/1541-7786.MCR-05-0085.
Roose J & Clevers H 1999 TCF transcription factors: molecular switches in carcinogenesis. Biochimica et Biophysica Acta 1424 M23–M37.doi:10.1016/S0304-419X(99)00026-8.
Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Höfler H & Becker KF 2002 Differential expression of the epithelial–mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. American Journal of Pathology 161 1881–1891.doi:10.1016/S0002-9440(10)64464-1.
Rosner IL, Ravindranath L, Furusato B, Chen Y, Gao C, Cullen J, Sesterhenn IA, McLeod DG, Srivastava S & Petrovics G 2007 Higher tumor to benign ratio of the androgen receptor mRNA expression associates with prostate cancer progression after radical prostatectomy. Urology 70 1225–1229.doi:10.1016/j.urology.2007.09.010.
Roy-Burman P, Tindall DJ, Robins DM, Greenberg NM, Hendrix MJ, Mohla S, Getzenberg RH, Isaacs JT & Pienta KJ 2005 Androgens and prostate cancer: are the descriptors valid? Cancer Biology and Therapy 4 4–5.
Sargeant AM, Rengel RC, Kulp SK, Klein RD, Clinton SK, Wang YC & Chen CS 2008 OSU-HDAC42, a histone deacetylase inhibitor, blocks prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate model. Cancer Research 68 3999–4009.doi:10.1158/0008-5472.CAN-08-0203.
Scher HI & Sawyers CL 2005 Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. Journal of Clinical Oncology 23 8253–8261.doi:10.1200/JCO.2005.03.4777.
Seaton A, Scullin P, Maxwell PJ, Wilson C, Pettigrew J, Gallagher R, O'Sullivan JM, Johnston PG & Waugh DJ 2008 Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation. Carcinogenesis 29 1148–1156.doi:10.1093/carcin/bgn109.
Seo YK, Zhu B, Jeon TI & Osborne TF 2009 Regulation of steroid 5-α reductase type 2 (Srd5a2) by sterol regulatory element binding proteins and statin. Experimental Cell Research 315 3133–3139.doi:10.1016/j.yexcr.2009.05.025.
Shabbeer S, Kortenhorst MS, Kachhap S, Galloway N, Rodriguez R & Carducci MA 2007 Multiple molecular pathways explain the anti-proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo. Prostate 67 1099–1110.doi:10.1002/pros.20587.
Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE & Witkiewicz AK et al. 2010 The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. Journal of Clinical Investigation 120 4478–4492.doi:10.1172/JCI44239.
Shigemura K, Shirakawa T, Wada Y, Kamidono S, Fujisawa M & Gotoh A 2005 Antitumor effects of etodolac, a selective cyclooxygenase-II inhibitor, against human prostate cancer cell lines in vitro and in vivo. Urology 66 1239–1244.doi:10.1016/j.urology.2005.06.076.
Shiota M, Yokomizo A, Tada Y, Inokuchi J, Kashiwagi E, Masubuchi D, Eto M, Uchiumi T & Naito S 2010 Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene 29 237–250.doi:10.1038/onc.2009.322.
Siu YT & Jin DY 2007 CREB – a real culprit in oncogenesis. FEBS Journal 274 3224–3232.doi:10.1111/j.1742-4658.2007.05884.x.
Skurk C, Maatz H, Kim HS, Yang J, Abid MR, Aird WC & Walsh K 2004 The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. Journal of Biological Chemistry 279 1513–1525.doi:10.1074/jbc.M304736200.
Sobel RE & Sadar MD 2005 Cell lines used in prostate cancer research: a compendium of old and new lines – part 1. Journal of Urology 173 342–359.doi:10.1097/01.ju.0000141580.30910.57.
Stacey DW, Hitomi M, Kanovsky M, Gan L & Johnson EM 1999 Cell cycle arrest and morphological alterations following microinjection of NIH3T3 cells with Purα. Oncogene 18 4254–4261.doi:10.1038/sj.onc.1202795.
Su-Hyeong K & Shivendra VS 2009 d,l-sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells. Molecular Cancer Therapeutics 8 1946–1954.doi:10.1158/1535-7163.MCT-09-0104.
Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM & Sun H et al. 2010 Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. Journal of Clinical Investigation 120 2715–2730.doi:10.1172/JCI41824.
Supakar PC, Jung MH, Song CS, Chatterjee B & Roy AK 1995 Nuclear factor κ B functions as a negative regulator for the rat androgen receptor gene and NF-κB activity increases during the age-dependent desensitization of the liver. Journal of Biological Chemistry 270 837–842.doi:10.1074/jbc.270.2.837.
Sweeney C, Li L, Shanmugam R, Bhat-Nakshatri P, Jayaprakasan V, Baldridge LA, Gardner T, Smith M, Nakshatri H & Cheng L 2004 Nuclear factor-κB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate. Clinical Cancer Research 10 5501–5507.doi:10.1158/1078-0432.CCR-0571-03.
Swinnen JV, Heemers H, van de Sande T, de Schrijver E, Brusselmans K, Heyns W & Verhoeven G 2004 Androgens, lipogenesis and prostate cancer. Journal of Steroid Biochemistry and Molecular Biology 92 273–279.doi:10.1016/j.jsbmb.2004.10.013.
Takane KK & McPhaul MJ 1996 Functional analysis of the human androgen receptor promoter. Molecular and Cellular Endocrinology 119 83–93.doi:10.1016/0303-7207(96)03800-2.
Taplin ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J, Stadler W, Hayes DF, Kantoff PW & Vogelzang NJ et al. 2003 Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. Journal of Clinical Oncology 21 2673–2678.doi:10.1200/JCO.2003.11.102.
Tepper CG, Vinall RL, Wee CB, Xue L, Shi XB, Burich R, Mack PC & de Vere White RW 2007 GCP-mediated growth inhibition and apoptosis of prostate cancer cells via androgen receptor-dependent and -independent mechanisms. Prostate 67 521–535.doi:10.1002/pros.20548.
Tian B & Brasier AR 2003 Identification of a nuclear factor κ B-dependent gene network. Recent Progress in Hormone Research 58 95–130.doi:10.1210/rp.58.1.95.
Tilley WD, Marcelli M & McPhaul MJ 1990 Expression of the human androgen receptor gene utilizes a common promoter in diverse human tissues and cell lines. Journal of Biological Chemistry 265 13776–13781.
Tiniakos DG, Mitropoulos D, Kyroudi-Voulgari A, Soura K & Kittas C 2006 Expression of c-Jun oncogene in hyperplastic and carcinomatous human prostate. Urology 67 204–208.doi:10.1016/j.urology.2005.07.045.
Titus MA, Schell MJ, Lih FB, Tomer KB & Mohler JL 2005 Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clinical Cancer Research 11 4653–4657.doi:10.1158/1078-0432.CCR-05-0525.
Vander Griend DJ, Antony L, Dalrymple SL, Xu Y, Christensen SB, Denmeade SR & Isaacs JT 2009 Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells. Molecular Cancer Therapeutics 8 1340–1349.doi:10.1158/1535-7163.MCT-08-1136.
Verras M & Sun Z 2006 Roles and regulation of Wnt signaling and β-catenin in prostate cancer. Cancer Letters 237 22–32.doi:10.1016/j.canlet.2005.06.004.
Wang X, Sato R, Brown MS, Hua X & Goldstein JL 1994 SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77 53–62.doi:10.1016/0092-8674(94)90234-8.
Wang LG, Ossowski L & Ferrari AC 2004 Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line. Oncogene 23 5175–5184.doi:10.1038/sj.onc.1207654.
Wang LG, Liu XM & Chiao JW 2006 Repression of androgen receptor in prostate cancer cells by phenethyl isothiocyanate. Carcinogenesis 27 2124–2132.doi:10.1093/carcin/bgl075.
Wang LG, Johnson EM, Kinoshita Y, Babb JS, Buckley MT, Liebes LF, Melamed J, Liu XM, Kurek R & Ossowski L et al. 2008 Androgen receptor overexpression in prostate cancer linked to Purα loss from a novel repressor complex. Cancer Research 68 2678–2688.doi:10.1158/0008-5472.CAN-07-6017.
Wu D, Zhau HE, Huang WC, Iqbal S, Habib FK, Sartor O, Cvitanovic L, Marshall FF, Xu Z & Chung LW 2007 cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis. Oncogene 26 5070–5077.doi:10.1038/sj.onc.1210316.
Xing N, Chen Y, Mitchell SH & Young CY 2001 Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis 22 409–414.doi:10.1093/carcin/22.3.409.
Yang F, Li X, Sharma M, Sasaki CY, Longo DL, Lim B & Sun Z 2002 Linking β-catenin to androgen-signaling pathway. Journal of Biological Chemistry 277 11336–11344.doi:10.1074/jbc.M111962200.
Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A & Weinberg RA 2004 Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117 927–939.doi:10.1016/j.cell.2004.06.006.
Yang L, Xie S, Jamaluddin MS, Altuwaijri S, Ni J, Kim E, Chen YT, Hu YC, Wang L & Chuang KH et al. 2005 Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells. Journal of Biological Chemistry 280 33558–33565.doi:10.1074/jbc.M504461200.
Yang X, Chen MW, Terry S, Vacherot F, Bemis DL, Capodice J, Kitajewski J, de la Taille A, Benson MC & Guo Y et al. 2006 Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells. Oncogene 25 3436–3444.doi:10.1038/sj.onc.1209366.
Yardy GW & Brewster SF 2005 Wnt signalling and prostate cancer. Prostate Cancer and Prostatic Diseases 8 119–126.doi:10.1038/sj.pcan.4500794.
Yeh S, Miyamoto H, Nishimura K, Kang H, Ludlow J, Hsiao P, Wang C, Su C & Chang C 1998 Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells. Biochemical and Biophysical Research Communications 248 361–367.doi:10.1006/bbrc.1998.8974.
Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL & Brown MS 1993 SREBP-1, a basic-helix–loop–helix–leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75 187–197.
Yu X, Wang Y, Degraff DJ, Wills ML & Matusik RJ 2010 Wnt/β-catenin activation promotes prostate tumor progression in a mouse model. Oncogene 30 1868–1879.doi:10.1038/onc.2010.560.
Yuan H, Pan Y & Young CY 2004 Overexpression of c-Jun induced by quercetin and resverol inhibits the expression and function of the androgen receptor in human prostate cancer cells. Cancer Letters 213 155–163.doi:10.1016/j.canlet.2004.04.003.
Yuan H, Gong A & Young CY 2005 Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells. Carcinogenesis 26 793–801.doi:10.1093/carcin/bgi021.
Yuan HQ, Kong F, Wang XL, Young CY, Hu XY & Lou HX 2008 Inhibitory effect of acetyl-11-keto-β-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells. Biochemical Pharmacology 75 2112–2121.doi:10.1016/j.bcp.2008.03.005.
Yuen HF, Chua CW, Chan YP, Wong YC, Wang X & Chan KW 2007 Significance of TWIST and E-cadherin expression in the metastatic progression of prostatic cancer. Histopathology 50 648–658.doi:10.1111/j.1365-2559.2007.02665.x.
Zegarra-Moro OL, Schmidt LJ, Huang H & Tindall DJ 2002 Disruption of androgen function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Research 62 1008–1013.
Zhang L, Charron M, Wright WW, Chatterjee B, Song CS, Roy AK & Brown TR 2004 Nuclear factor-κB activates transcription of the androgen receptor gene in Sertoli cells isolated from testes of adult rats. Endocrinology 145 781–789.doi:10.1210/en.2003-0987.
Zhang Y, Wang XW, Jelovac D, Nakanishi T, Yu MH, Akinmade D, Goloubeva O, Ross DD, Brodie A & Hamburger AW 2005 The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells. PNAS 102 9890–9895.doi:10.1073/pnas.0503829102.
Zhang L, Altuwaijri S, Deng F, Chen L, Lal P, Bhanot UK, Korets R, Wenske S, Lilja HG & Chang C et al. 2009 NF-κB regulates androgen receptor expression and prostate cancer growth. American Journal of Pathology 175 489–499.doi:10.2353/ajpath.2009.090275.
Zhao XY, Ly LH, Peehl DM & Feldman D 1999 Induction of androgen receptor by 1α,25-dihydroxyvitamin D3 and 9-cis retinoic acid in LNCaP human prostate cancer cells. Endocrinology 140 1205–1212.doi:10.1210/en.140.3.1205.
Zhao H, Whitfield ML, Xu T, Botstein D & Brooks JD 2004 Diverse effects of methylseleninic acid on the transcriptional program of human prostate cancer cells. Molecular Biology of the Cell 15 506–519.doi:10.1091/mbc.E03-07-0501.
Zhou Z, Flesken-Nikitin A, Corney DC, Wang W, Goodrich DW, Roy-Burman P & Nikitin AY 2006 Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Research 66 7889–7898.doi:10.1158/0008-5472.CAN-06-0486.
