• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Expert Rev Endocrinol Metab. Author manuscript; available in PMC Jul 1, 2011.
Published in final edited form as:
Expert Rev Endocrinol Metab. Sep 2010; 5(5): 753–764.
doi:  10.1586/eem.10.49
PMCID: PMC3035007

Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer


Hormone therapies targeting androgen receptor signaling are the mainstay of treatment for patients with advanced prostate cancer. The length of clinical remission induced by hormone therapies varies substantially among treated patients. Why some patients progress rapidly after treatment while others benefit with prolonged remission is a question that remains unsolved. The androgen receptor signaling pathway is the key molecular determinant of castration resistance, and a key target for prostate cancer drug design. Recent advances in characterizing molecular processes leading to the development of castration-resistant prostate cancer, including the discovery of multiple androgen receptor splicing variants, offer opportunities for rational development of new clinical tools or approaches to predict, monitor or control/prevent prostate cancer progression in the castrate setting.

Keywords: androgen receptor, AR, AR signaling, AR splicing variants, castration-resistant prostate cancer, CRPC, hormone therapy, prostate cancer

In 1941, Huggins and Hodges demonstrated the clinical efficacy of hormonal manipulation for the treatment of metastatic prostate cancer [1]. Androgen suppression therapies (ASTs) have since become the mainstay of systemic treatment for advanced prostate cancer. The clinical benefits of androgen suppression are well established when AST is applied in the setting of metastatic disease [2]. Most patients respond to AST by entering into clinical remission, although they eventually experience disease relapse and develop more aggressive tumors, commonly termed ‘hormone-refractory prostate cancer’ or ‘castration-resistant prostate cancer’ (CRPC). In addition to its standard use in patients with metastatic disease, AST is increasingly being applied to prostate cancer patients with a wide spectrum of clinical phenotypes, including men experiencing biochemical recurrence after definitive primary treatment (e.g., radiation or surgery) [3], indicated by a re-elevation of serum prostate-specific antigen (PSA) but no other evidence of disease. Annually, an estimated 70,000 men in the USA alone develop biochemical recurrence [4], which is a source of patient anxiety that often provokes consideration of AST treatment options [5].

This widespread use of AST in patients with advanced prostate cancer has prompted a debate regarding the clinical benefit associated with early (before the onset of clinical metastasis) versus late AST, a subject of investigation in numerous ongoing clinical trials [6]. Given that the efficacy of AST is limited by time and the severe side effects are additive with longer duration of AST, these clinical trials seek to determine the optimal timing of AST in various clinical settings [6]. Some clinical trials have provided evidence supporting the survival benefit of early ASTs; however, such benefits have been relatively well established in only a subset of patients [3,7,8], suggesting that the clinical benefit may vary among patients in different disease and treatment categories. Even among men with metastatic prostate cancer, for which AST is the established standard of care, the length of clinical remission induced by AST can range from months to more than 10 years [9]. Among those relapsed patients (i.e., CRPC patients), a subset (~30–60%) may continue to benefit from sequential second-line hormone therapies [1014]. Although clinical parameters [3,8,15] may provide some prognostic utility in these treatment settings, there are currently no definitive clinical methods that can reliably predict responses to first- or second-line therapies. Therefore, although ASTs have been in use for 70 years, why some patients progress rapidly after treatment while others benefit with prolonged remission is still an unsolved question.

Endocrine approaches to the treatment of advanced prostate cancer have evolved over the last 30 years [16], yet the common therapeutic target remains the same. All existing endocrine therapies (Figure 1), including those currently under Phase III trials for the treatment of CRPC (e.g., MDV3100 and abiraterone), target the androgen receptor (AR) signaling pathway [1114]. More precisely, a specific domain of the AR, the ligand-binding domain (LBD), is the intended target of all hormone therapy regimens (Figure 1). The importance of the AR as the key target for prostate cancer therapeutic development is supported by the prevailing explanation for endocrine therapy failure – sustained AR signaling despite castrate levels of androgens [16].

Figure 1
Hormone therapy regimens commonly used to treat advanced prostate cancer

Multiple molecular processes contributing to sustained AR signaling in a castrate setting have been proposed and reviewed extensively [1719]. Somatic androgen receptor mutations [20], AR gene amplification [21] and AR overexpression [22] may sensitize the AR to reduced levels of androgens or agonizing anti-androgens in CRPC. AR signaling is also enhanced by alterations in AR coactivators and corepressors [23], AR post-translational modifications [24] or AR cross-talk with other signaling molecules [25]. Under these mechanisms, AR signaling still requires, or is enhanced by, ligand binding to the AR LBD. With regard to the requirement for ligand binding, it is also known that existing androgen-suppression regimens do not lead to complete ablation of androgens, and that prostate cancer cells may synthesize androgens de novo or from adrenal androgen precursors [26]. Recently, we and others reported the discovery of multiple novel ARs that lack the LBD [2729]. These ARΔLBD variants are constitutively active (i.e., active in the absence of androgens) and mediate AR signaling, which is not targeted by any of the existing hormone therapy regimens (Figure 1). In addition, we detected elevated levels of the AR variants (by ~20 fold) in CRPC tissues, suggesting an alternative and potentially more direct explanation for hormone therapy resistance [2729].

In this article, we will evaluate the evidence supporting each of the above mechanisms, with a focus on mechanisms evolving to activate the AR signaling pathway in the castrate setting. We will also evaluate other mechanisms that bypass the requirement of AR signaling, as well as a complex immune-mediated model of castration resistance. Many of the key mechanisms are currently driving the development of novel therapies to treat CRPC. However, a lack of therapeutic response indicators is a clear limiting factor in the development of novel endocrine therapies for advanced prostate cancer. We discuss the implications of these recent research advances in addressing this unmet need in the management of advanced prostate cancer.

Molecular components of AR signaling

The biological effect of androgens is mediated through the AR, a member of the nuclear steroid hormone receptor super family. The human AR coding sequence was cloned in 1988, in three independent laboratories [3032]. The cloning of human AR made it possible to study AR structure and function. The AR gene is located on the X chromosome (Xq11–12), spanning approximately 180 kb of DNA with eight canonical exons (exon 1–8) [33]. Like other nuclear steroid hormone receptors (e.g., estrogen receptor and progesterone receptor), the AR protein is organized into four discrete functional domains, an N-terminal domain (NTD), a highly conserved DNA-binding domain (DBD), a short hinge region and a moderately conserved C-terminal LBD [32,33]. Figure 2 illustrates the chromosomal organization and structure of the AR gene, the AR mRNA transcript and the AR protein domains. The AR NTD, encoded by exon 1, constitutes nearly 60% of the AR protein sequence and harbors a majority of the AR transcriptional activities and AR coactivator interaction interface [34]. The cysteine-rich AR DBD is composed of two zinc finger motifs, which are encoded by exon 2 and exon 3, respectively. The first zinc finger motif mediates the recognition of the specific nucleotide in the AR response element and facilitates DNA binding. The second zinc finger stabilizes the DNA binding. The hinge region, encoded by part of exon 4, contains a bipartite nuclear localization signal as well as important sites for phosphorylation, acetylation and degradation. The LBD, encoded by part of exon 4 and exons 5–8, mediates ligand binding [3538]. Crystal structure of the AR LBD demonstrated that the C-terminus amino acids of AR assume a ligand-binding pocket by the ordered arrangement of 12 conserved α-helices [33,39].

Figure 2
The human androgen receptor gene, transcript and protein structure

Upon ligand binding, the AR undergoes a conformational change to a more active form, allowing subsequent nuclear translocation, homodimer formation and DNA binding [39]. Subsequent to AR binding to the AR response elements located on the target gene, essential AR cofactors (coactivators and/or corepressors) are recruited to the transcriptional machinery, which regulates gene transcription [40]. To date, more than 170 AR cofactors have been identified. Coactivators enhance and corepressors reduce the AR transactivation function by direct regulation of transcriptional control through physical interaction with general transcription factors and RNA polymerase, facilitating AR DNA binding and chromatin remodeling, and changing AR folding and AR subcellular localization [39,41].

AR gene amplification and AR overexpression in CRPC

AR gene amplification was first reported in the early 1990s [21]. Since then, the reported incidence of AR gene amplification has varied between 20 and 33% in CRPC patients, but very few cases have been reported in untreated primary prostate cancer [21,42]. Very recently, AR amplification was examined in circulating tumor cells derived from patients undergoing second-line hormone therapies [43,44]. These studies revealed a much higher rate (50–85%) of AR copy number gain in CRPC patients. The variation of the assessed AR amplification rate in the recurrent prostate cancer specimens could be explained by cohort differences, tumor heterogeneity and technical limitations in the early 1990s. The fact that AR gene amplification was rarely detected in the primary prostate tumor suggests that AR gene amplification contributes to the development of CRPC. Amplification of the wild-type AR (i.e., no mutations) was associated with a substantially increased level of AR mRNA and protein [42,45], although increased AR protein cannot be completely explained by AR gene amplification alone [4547]. Interestingly, AR amplification was more frequently observed in patients who initially responded to hormone therapies and later gradually developed resistance, but was rarely seen in those who displayed no initial response to androgen deprivation or those who developed resistance in less than 12 months [42].

Since existing hormone therapy regimens do not completely deplete androgens, an increased level of wild-type AR protein as a result of AR gene amplification or other mechanisms may confer an elevated response to a diminished level of testosterone or dihydrotestosterone (DHT), therefore, causing a survival and growth advantage upon castration. Based on the finding that the AR gene is the only gene consistently upregulated during progression to CRPC in multiple xenograft models, Chen et al. presented evidence supporting increased AR expression being both required and necessary for the progression of prostate cancer to a castration-resistant state [22]. In addition, an increased AR level can convert an AR antagonist (the anti-androgen bicalutamide) to an agonist [22], suggesting an alternative explanation (other than AR mutation, see later) for the well-known paradox termed ‘anti-androgen withdrawal response’ [48], in which tumor regression was observed in approximately 50% of patients undergoing complete androgen blockade (luteinizing hormone-releasing hormone analog plus anti-androgen) following discontinuation of anti-androgens. This pivotal study by Chen et al. has motivated the search for second-generation anti-androgens with greater affinity, using cells that overexpress AR. Examples of second-generation anti-androgens include RD162 and MDV3100 [11]. Both compounds inhibit AR nuclear localization, AR DNA binding and AR coactivator recruitment [11]. MDV3100 is currently under Phase III clinical trials for the treatment of CRPC [11,14,49,50]. Another example of a second-generation anti-androgen that is currently in Phase I clinical trials is TOK-001 (VN/124-1) [51,52]. TOK-001 possesses several anticancer properties that target the AR: direct AR antagonism, androgen suppression via CYP17 inhibition (see later) and AR protein downregulation [51,52]. Interestingly, TOK-001 also inhibits growth of AR-negative prostate cancer cells.

A general consensus that further supports the importance of AR expression in CRPC is that increased AR protein expression is characteristic of aggressive prostate cancer in various disease settings. However, study results that rely on immunohistochemical (IHC) assessment of AR expression need to be interpreted with caution, as differences in the performance of the anti-AR antibody as well as tissue processing methods related to the specific treatment setting can dramatically influence the results. Higher AR expression was observed in more aggressive prostate tumors when compared with less aggressive tumors, and thus may serve as a prognostic IHC marker in patients treated with surgery [53,54]. Using tissue IHC data, Donovan et al. demonstrated that AR levels at baseline (i.e., detected at the time of surgical treatment but prior to hormone therapy) were positively associated with shorter time to PSA progression after AST [53]. However, IHC studies in CRPC specimens did not show significant correlation between AR protein expression level and patient survival [46,55,56]. A recent study found significantly lower AR protein expression in the metastatic CRPC tumors compared with the primary prostate tumor [57]. It is worth noting that in this study, an AR antibody specific to the AR LBD was used, therefore detecting only full-length AR proteins with an intact LBD. In light of the presence of multiple AR splicing variants that lack the AR LBD (see later) [2729], future studies comparing results derived from the use of multiple AR antibodies may reveal findings suggestive of the relative importance of the full-length AR and the AR variants.

AR gene mutation

Androgen suppression therapy also seems to confer a selection pressure for somatic AR gene mutations because AR gene mutations were found in a higher frequency in patients with more advanced disease [5864]. Many AR gene mutations have been reported in prostate cancer tissues and are summarized together with AR gene mutations associated with other endocrine diseases in the McGill Androgen Receptor Gene Mutation Database [65]. The AR gene mutations in the LBD may alter ligand binding, leading to AR activation by AR antagonists and other ligands that do not activate wild-type AR. AR LBD mutations may explain the paradoxical anti-androgen withdrawal response, manifested as PSA decline and tumor regression in a substantial proportion of CRPC patients receiving combined androgen blockade (luteinizing hormone-releasing hormone and anti-androgen therapies) after the agonist activities of the anti-androgens were removed [48]. Therefore, this gain-of-function mutation may lead to a growth advantage in the absence of sufficient AR natural ligands, or the presence of anti-androgens. For example, the first characterized AR gene mutation T877A was found in both LNCaP prostate cancer cells and in clinical tissues. AR-T877A can be activated by androgens, the AR antagonist flutamide, estrogens and progesterone [18,66,67]. This broadened ligand-binding capability of AR-T877A to progesterone has been confirmed by crystallographic studies [68,69]. However, subsequent investigations found no association between AR mutations detected in bone marrow specimens from CRPC patients with either anti-androgen withdrawal response or survival [60].

It is a general consensus that the incidence of AR mutation is relatively low (~10%) in CRPC specimens. As such, the role of the AR mutations in CRPC progression is not clear [61,63]. Technical limitations may explain some of the discrepancies in previously reported AR mutation rates [20,70]. It remains possible that a higher mutation rate might be revealed using more comprehensive approaches such as next-generation sequencing technologies, although such studies will almost certainly reveal the diversity and intratumor heterogeneity of various AR mutations, among which only a subset have been functionally characterized [20,58,59,71].

All naturally occurring AR mutants characterized so far contain a LBD (thus, they still require the presence of ligands for AR signaling) with one exception. Ceraline et al. isolated an AR mutant – Q640X. AR-Q640X does not contain a LBD owing to a nonsense mutation immediately after the coding sequences for the DBD. This mutant mediates AR signaling independent of any ligands [72]. The prevalence of this constitutively active AR mutant in CRPC, however, has yet to be fully characterized.

AR splicing variants

Shortly following the cloning of human AR in 1988, a number of laboratories generated AR deletion mutants with intact NTDs and DBDs but lacking LBDs [37,73]. These artificially generated ARΔLBD variants were demonstrated to be constitutively active. Although findings from Ceraline et al. provided one example that such variants could occur naturally through a simple mutation [72], similar mutations have not been verified. As a result, it is impossible to reliably detect the ARΔLBD variants in clinical specimens. Recent discoveries of naturally occurring AR variants derived from alternative splicing made it possible to detect and study ARΔLBD variants [2729]. These studies, including one from our group, suggest that AR signaling could occur in the complete absence of ligand binding, owing to the expression of constitutively active ARΔLBD variants. These AR variants are encoded by newly discovered AR transcripts with ‘intronic’ insertions (i.e., cryptic exons) downstream of the coding sequences for the AR DBD. Owing to the premature stop codons present in those cryptic exons, the translated AR proteins are truncated, retaining the NTD, DBD and a short variant-specific peptide, but lacking the LBD. These ARΔLBD variants mediate genomic functions despite the absence of androgens or the presence of anti-androgens. The functional differences between the wild-type full-length AR and the AR variants are illustrated in Figure 3.

Figure 3
Differences in AR signaling mediated by the full-length AR with intact LBD, and an AR variant that lacks LBD

The clinical relevance of these truncated AR variants has also been characterized. Such studies were made possible by variant-specific mRNA probes that detect the AR variants but not the full-length AR, or vice versa, as well as antibodies developed against variant-specific peptides. Significantly elevated expression of the AR variants, measured at both the mRNA and protein levels, was detected in CRPC specimens, as well as in a subset of prostate specimens from untreated (i.e., hormone naive) patients who experienced biochemical recurrence after radical prostatectomy [28,29]. Thus, progressive acquisition of ligand-independent AR signaling, through AR splicing, may occur during prostate cancer progression in both castrate and noncastrate conditions. Collectively, these studies provide strong evidence supporting an alternative and potentially more direct explanation for castration resistance in prostate cancer.

The relative importance of the seven ARΔLBD variants we reported in our study [29] has been further characterized in more detail. The seven AR variants are named numerically, from AR-V1 to AR-V7, according to the genomic positions of the variant-specific intronic sequences. The two AR transcript variants identified by Dehm et al., named AR1/2/2b and AR1/2/3/2b [27], contain transcribed ‘intronic’ sequences identical to those in AR-V3 and AR-V4, respectively. The three AR variant transcripts identified by Guo et al., named AR3, AR4 and AR5 in that study [28], contain transcribed ‘intronic’ sequences identical to those in AR-V7, AR-V1 and AR-V4, respectively. Therefore, the seven AR variants identified in our study match all those reported in other studies. Preliminary data presented in Table 1 summarize the diverse characteristics among the seven AR variants in terms of their abundance in clinical specimens, their suitability for antibody development and their functional activities.

Table 1
Clinical relevance, functional relevance and other characteristics of the seven AR variants.

While the discovery of the AR variants made it possible to detect them in clinical specimens, whether these discoveries can be translated into the clinical setting as molecular indicators of therapeutic response awaits further investigation. Carefully designed studies addressing whether AR variant expression levels can be used to predict or indicate hormone therapy response have not yet been performed. While the detection methods are being developed and can be optimized for these purposes, such studies entail the application of the detection methods in a clinical cohort that is uniformly managed and followed up after endocrine therapy regimens. Existing clinical trials assessing the second-line hormone therapies may provide the platform for such studies.

Role of AR cofactors

Alterations in AR coregulator levels and function may contribute to the development of CRPC. Studies regarding the AR cofactors in prostate cancer have been reviewed previously [23]. Upregulation of coactivators was proposed as a mechanism to sensitize the AR to low-level androgens [49]. For example, several AR coactivators, including TIF2, SRC1 and TIP60, are overexpressed in CRPC [74,75]. In the presence of overexpressed TIF2, AR signaling was activated by physiological concentrations of adrenal androgens [74]. Depletion of TIF2 reduced the AR target gene expression and also slowed down the proliferation of both AR-dependent and AR-independent prostate cancer cells [76]. Clinicopathological studies also showed that aberrant expression of several AR cofactors was associated with poor prognosis [23]. Heemers et al. showed that androgen controls approximately over 30% of cofactor genes in prostate cancer cells [77], suggesting that a coordinated AR and AR cofactor network regulates AR signaling.

Cross-talk with growth factor signaling pathways & AR phosphorylation

The cross-talk between growth factor and AR signaling pathways in prostate cancer cells has been well documented. Considerable evidence supports the ability of growth hormones and cytokines to activate AR. For example, IL-6, KGF, EGF and IGF-1 can each stimulate AR target gene expression in the absence of the AR ligand [7880]. Evidence from these studies also suggests that the MAPK and PI3K/AKT pathways may be the mediating pathways [78,79]. Importantly, expression levels of IGF-1, IL-6 and EGF are elevated during progression to CRPC [8183]. Activation of the MARK and PI3K/AKT pathway may result in phosphorylation of AR coactivators, such as SRC-1 and TIF2 [78,79], or the AR protein itself (see later).

Androgen receptor agonists induced AR phosphorylation at the seven serine residues (serines-16, -94, -81, -256, -308, -424 and -650) [84]. R1881 treatment leads to phosphorylation of all these serine sites except serine-94, which is constitutively phosphorylated. Evidence of direct phosphorylation of AR by growth factors has been presented. The expression of HER2/neu, a member of the EGF receptor family, is increased in a subset of hormone-refractory LAPC4 xenografts and overexpression of HER2 in androgen-dependent prostate cancer cells promotes androgen-independent cell growth [85]. Yeh et al. have shown that AR can be phosphorylated by MAPK, which mediates AR transactivation by HER2/neu [86]. PTEN tumor-suppressor gene is frequently mutated and functionally inactivated in metastatic CRPC [87]. With loss of PTEN function, AKT activity is enhanced and promotes prostate tumor growth in castrated mice [88]. AKT binds to AR and phosphorylates serine-210 and serine-790 [89,90]. AKT activation provides additional pathways that mediate activation of AR by HER2/neu, as blocking of the AKT pathway abrogates the HER2/neu-induced AR signaling in the absence of androgens [90]. AR serine phosphorylation by MAPK or AKT may sensitize AR to low levels of DHT [91]. Increased levels of phosphorylated AKT (pAKT473) and phosphorylated AR (pAR210) during the transition from hormone-naive to castration-resistant prostate cancer has been associated with shortened disease-specific survival [92].

In addition to serine and thereonine AR phosphorylation, AR tyrosine phosphorylation has been reported [9395]. AR can be phosphorylated at tyrosine-534 by Src tyrosine kinase in response to several growth factors, including EGF, heregulin and IL-6 [93,94], or at tyrosine-267 and tyrosine-363 by Ack1 [95]. AR phosphorylation at tyrosine-267 regulates androgen-independent recruitment of AR to the androgen-responsive enhancers and transcription of AR target genes in the absence of androgens [95,96]. In clinical specimens, an increase of Src family kinase activity during the development of CRPC is associated with worse treatment outcomes [97].

Studies of AR signaling cross-talk in CRPC have led to clinical studies targeting IL-6, IGF receptors, EGF receptor and Src kinase in the treatment of CRPC [98100].

Intracrine androgen production

Castration blocks gonadal testosterone synthesis, but androgens can also be synthesized from adrenal androgens in prostate tissues using steroidogenic enzymes expressed in target cells [101,102]. Initial studies carried out in animal models demonstrated that by increasing the serum dehydroepiandrosterone concentrations in castrated animals, prostate weight and intraprostatic DHT levels were elevated compared with the control castrated animals [101]. It was assessed that approximately 40% of androgens in men are produced by peripheral target tissue from adrenal steroid precursors [102]. In addition to adrenal androgens, prostate cancer cells may produce androgens de novo. Dillard et al. demonstrated for the first time that high-passage LNCaP cells are able to synthesize testosterone from cholesterol without depending on testicular and/or adrenal androgens [103]. Locke et al. showed that tumor explants isolated from CRPC tumors in LNCaP xenografts were capable of de novo conversion of [14C]acetic acid to DHT, using an ex vivo radiotracing assay coupled to HPLC radiometric/mass spectrometry detection [104]. In clinically relevant settings, Geller et al. reported for the first time that castration did not completely eliminate prostate cancer tissue DHT levels [105]. Studies from Mohler et al. confirmed these findings by measuring intraprostatic tissue testosterone and DHT levels in CRPC patients [106,107]. In these studies, DHT levels in the prostate tissues collected after androgen ablation therapy were decreased substantially (by 91% in one study and 82% in another study carried out by the same group, compared with hormone-naive benign prostate), yet at a level sufficient to activate AR. Interestingly, intraprostatic testosterone levels remained at similar levels after ASTs [106,107]. Studies from Nishiyam et al. also demonstrated that after androgen deprivation therapy, prostatic DHT levels remained at approximately 75% of the pretreatment levels [108,109]. Other evidence supporting the role of intracrine tumor androgen synthesis is the upregulation of enzymes involved in androgen synthesis in the CRPC specimens [104,110,111]. However, simultaneous expression of the enzymes CYP17A1 and HSD3B1, both of which are essential for the synthesis of androgens from pregnenolone, can only be detected in a small portion of the castration prostate cancer tissues [112].

Based on the overall evidence presented above, it seems plausible to inhibit testicular, adrenal and intracrine androgen sources by targeting the metabolic enzymes in CRPC patient management [113]. CYP17 is one of the key enzymes in androgen synthesis in both adrenal gland and tumor tissues [114,115]. CYP17 consists of two enzymatic components, 17-α hydroxylase and C17,20-lyase. The former enzyme converts pregnenolone to 17α-hydroxypregnenolone and progesterone to 17-α hydoxyprogesterone. The latter converts 17α-hydroxypregnenolone to dehydroepiandrosterone, and 17-α hydoxyprogesterone to androstenedione [114,116]. Abiraterone is a potent CYP17 inhibitor. A Phase III trial evaluating abiraterone in the treatment of CRPC is ongoing [49,115,117]. Another example of a CYP17/20-lyase inhibitor that is under clinical trial (Phase I/II) is TAK-700 [201].

Other pathways that bypass the AR signaling

Proposed molecular mechanisms leading to CRPC can be summarized into two broad categories: those that still require signaling through the AR, and those that bypass the dependence on AR signaling. While multiple lines of compelling evidence have established that, in most cases, CRPC does not lose dependence on AR signaling but instead is characterized by sustained AR signaling despite castrate levels of serum testosterone (<0.2 ng/ml) [118], it is also known that prostate cancer cells may evolve mechanisms to bypass the AR signaling pathway. Pathways that bypass AR signaling mainly operate in rare tumors with distinctive morphologies, such as neuroendocrine tumors and small cell carcinoma [119]. Approximately 10% of prostate cancer tumors show significant neuroendocrine (NE) differentiation, which can be induced by androgen ablation [120]. NE cells produce a number of growth factors, including serotonin and bombesin, that promote the growth of near-by exocrine tumor cells via paracrine mechanisms [121,122]. Although NE differentiation often escapes clinical detection because NEs do not make PSA, it may contribute significantly to the development of CRPC due to its multiple drug-resistance features [120]. The NE pathway can be targeted by somatostatin analogs and has been explored in clinical trials showing objective clinical responses [123125].

Overexpression of BCL-2, an anti-apoptotic gene, is another proposed AR-bypassing pathway mediating the development of CRPC. BCL-2 is not normally expressed in the secretary prostate epithelial cells, but is expressed in CRPC [126128]. Inhibition of BCL-2 with antisense oligonucleotide prevented the emergence of CRPC in xenograft models [129]. IHC studies have demonstrated increased BCL-2 expression in CRPC specimens compared with hormone-naive prostate cancer tissues [127,128]. Docetaxel, the first US FDA-approved chemotherapy for CRPC, phosphorylates and inactivates BCL-2 [100].

Role of inflammation in CRPC

In addition to the cell-autonomous mechanisms leading to the development of CRPC proposed above, a complex immune-mediated model of CRPC has been investigated. Approximately 20% of human cancers are caused by chronic inflammation [130]. Recent studies provide evidence supporting the role of inflammation in prostate cancer progression in the castrate setting. It was recently shown that inflammatory responses triggered by the death of androgen-deprived primary cancer cells contribute to progression to CRPC by activating I-κ-B kinase-β (IKK-β) in B cells, which leads to the production of cytokines that subsequently activate I-κ-B kinase-α (IKK-α) and STAT3 in the target cancer cells to enhance cell survival in androgen-deprived conditions [131]. In addition, activation of NF-κB, a key mediator of inflammation, may result in constitutive AR activation [132]. Cyclooxygenase-2 (COX-2) is a proinflammatory enzyme necessary for prostaglandin synthesis. Analysis of data from the Radiation Therapy Oncology Group (RTOG 92–02) trial concluded that increased COX-2 expression was significantly associated with biochemical failure, distant metastasis and any failure in patients treated with androgen deprivation plus radiotherapy [133]. Use of COX-2 inhibitors combined with androgen therapy has been evaluated in clinical trials targeting patients with biochemical recurrence [134].

Expert commentary & five-year view

Multiple mechanisms have been proposed to explain the development of CRPC subsequent to ASTs. Sustained AR signaling despite castrate levels of androgens still remains the key mechanism for CRPC development. Future treatment regimens for CRPC will focus on effective inhibition of AR signaling. The existence of constitutively active AR splicing variants implies that existing regimens will not be sufficient to completely suppress AR signaling. Translational development of novel approaches targeting the AR splicing variants awaits further knowledge regarding the relative contribution of the AR variants and the full-length AR to the development of CRPC, as well as more detailed profiling and characterization of additional AR splicing variants that are yet to be discovered. A more complete understanding of the role of intracrine androgens in CRPC is needed. The complex immune-mediated model of CRPC will stimulate clinical trials combining immune therapy and hormone therapy given the recent FDA approval of sipuleucel-T (Provenge, Dendreon, WA, USA), the first immune therapy for metastatic prostate cancer.

The current trend in managing patients with advanced prostate cancer emphasizes the importance of the AR signaling pathway and its implications in disease management. In addition to the standard use in patients with metastatic disease, AST is increasingly being used in patients with a wide spectrum of clinical phenotypes. A substantial proportion of patients who failed first-line hormone therapies may continue to benefit from sequential second-line hormone therapies [1012]. The relatively long treatment history of these patients in a contemporary clinical setting will drive the use of second-line endocrine approaches for the treatment of CRPC. Due to the lack of definitive clinical methods that predict individual responses, objective criteria have not been established to guide if and when to commence first-line or second-line hormone therapies. The development of molecular indicators of castration resistance may address this unmet need in the clinical management of patients with advanced prostate cancer and in clinical trials assessing novel endocrine therapies. Given that the efficacy of AST is limited by time and the severe side effects are additive with a longer duration of AST, as well as the modest survival benefit with nonhormonal treatments, better characterization of appropriate candidates for the less toxic and potential beneficial effects of secondary hormonal therapies could provide a valuable tool for patients and clinicians.


For reprint orders, please contact moc.sweiver-trepxe@stnirper

Financial & competing interests disclosure

Jun Luo received funding from the David H Koch Foundation, and the Patrick C Walsh Prostate Cancer Research Fund for his research on advanced prostate cancer. The Johns Hopkins University has filed an international patent for using androgen receptor variants as biomarkers and therapeutic targets for advanced prostate cancer. Rong Hu and Jun Luo are co-inventors of this pending patent. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.


Papers of special note have been highlighted as:

• of interest

•• of considerable interest

1. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;167(2 Pt 2):948–951. [PubMed]
2. Nesbit RM, Baum WC. Endocrine control of prostatic carcinoma; clinical and statistical survey of 1,818 cases. J Am Med Assoc. 1950;143(15):1317–1320. [PubMed]
3. Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol. 2008;179(5 Suppl):S53–S59. [PubMed]
4. Freedland SJ, Moul JW. Prostate specific antigen recurrence after definitive therapy. J Urol. 2007;177(6):1985–1991. [PubMed]
5. Dale W, Hemmerich J, Bylow K, Mohile S, Mullaney M, Stadler WM. Patient anxiety about prostate cancer independently predicts early initiation of androgen deprivation therapy for biochemical cancer recurrence in older men: a prospective cohort study. J Clin Oncol. 2009;27(10):1557–1563. [PMC free article] [PubMed]
6. Maroni PD, Crawford ED. The benefits of early androgen blockade. Best Pract Res Clin Endocrinol Metab. 2008;22(2):317–329. [PubMed]
7. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7(6):472–479. [PubMed]
8. D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008;299(3):289–295. [PubMed]
9•• . Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339(15):1036–1042. Reports the results from a landmark clinical trial that did not show survival benefit of anti-androgens. [PubMed]
10. Small EJ, Ryan CJ. The case for secondary hormonal therapies in the chemotherapy age. J Urol. 2006;176(6 Pt 2):S66–S71. [PubMed]
11. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787–790. [PMC free article] [PubMed]
12. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27(23):3742–3748. [PMC free article] [PubMed]
13. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26(28):4563–4571. [PubMed]
14. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a Phase 1–2 study. Lancet. 2010;375(9724):1437–1446. [PMC free article] [PubMed]
15. Smaletz O, Scher HI. Outcome predictions for patients with metastatic prostate cancer. Semin Urol Oncol. 2002;20(2):155–163. [PubMed]
16••. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009;10(10):981–991. Excellent review of the various hormone therapy regimens applied in different clinical settings. [PMC free article] [PubMed]
17. Knudsen KE, Penning TM. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab. 2010;21(5):315–324. [PMC free article] [PubMed]
18. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1(1):34–45. [PubMed]
19. Nacusi LP, Tindall DJ. Androgen receptor abnormalities in castration-recurrent prostate cancer. Expert Rev Endocrinol Metab. 2009;4(5):417–422. [PMC free article] [PubMed]
20. Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332(21):1393–1398. [PubMed]
21. Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9(4):401–406. [PubMed]
22••. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33–39. Demonstrates that increased androgen receptor (AR) expression is both required and necessary for the progression of prostate cancer to a castration-resistant state and that increased AR levels can convert an AR antagonist to an agonist. [PubMed]
23. Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer. 2007;120(4):719–733. [PubMed]
24. Xu K, Shimelis H, Linn DE, et al. Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell. 2009;15(4):270–282. [PMC free article] [PubMed]
25. Kaarbo M, Klokk TI, Saatcioglu F. Androgen signaling and its interactions with other signaling pathways in prostate cancer. Bioessays. 2007;29(12):1227–1238. [PubMed]
26. Mostaghel EA, Nelson PS. Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metab. 2008;22(2):243–258. [PMC free article] [PubMed]
27•• . Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008;68(13):5469–5477. This study, for the first time, cloned AR variants that are naturally ocurring. [PMC free article] [PubMed]
28. Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69(6):2305–2313. [PMC free article] [PubMed]
29••. Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69(1):16–22. This study discovered and characterized seven AR splicing variants in clinical specimens, and presented definitive evidence that AR-V7 has a translated protein product in both cell line and prostate cancer specimens. [PMC free article] [PubMed]
30. Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science. 1988;240(4850):324–326. [PubMed]
31. Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science. 1988;240(4850):327–330. [PubMed]
32. Trapman J, Klaassen P, Kuiper GG, et al. Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commun. 1988;153(1):241–248. [PubMed]
33•. Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol. 2002;20(13):3001–3015. Summarizes AR structure and the role of AR in prostate cancer. [PubMed]
34. Simental JA, Sar M, Lane MV, French FS, Wilson EM. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem. 1991;266(1):510–518. [PubMed]
35. Tanner T, Claessens F, Haelens A. The hinge region of the androgen receptor plays a role in proteasome-mediated transcriptional activation. Ann NY Acad Sci. 2004;1030:587–592. [PubMed]
36. Saporita AJ, Zhang Q, Navai N, et al. Identification and characterization of a ligand-regulated nuclear export signal in androgen receptor. J Biol Chem. 2003;278(43):41998–42005. [PubMed]
37. Zhou ZX, Sar M, Simental JA, Lane MV, Wilson EM. A ligand-dependent bipartite nuclear targeting signal in the human androgen receptor. Requirement for the DNA-binding domain and modulation by NH2-terminal and carboxyl-terminal sequences. J Biol Chem. 1994;269(18):13115–13123. [PubMed]
38. Zhou ZX, Kemppainen JA, Wilson EM. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol Endocrinol. 1995;9(5):605–615. [PubMed]
39. Li J, Al-Azzawi F. Mechanism of androgen receptor action. Maturitas. 2009;63(2):142–148. [PubMed]
40. Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002;23(2):175–200. [PubMed]
41. Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 2007;28(7):778–808. [PubMed]
42. Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57(2):314–319. [PubMed]
43. Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–2918. [PubMed]
44. Leversha MA, Han J, Asgari Z, et al. Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res. 2009;15(6):2091–2097. [PMC free article] [PubMed]
45. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res. 2001;61(9):3550–3555. [PubMed]
46. Ford OH, 3rd, Gregory CW, Kim D, Smitherman AB, Mohler JL. Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol. 2003;170(5):1817–1821. [PubMed]
47. Edwards J, Krishna NS, Grigor KM, Bartlett JM. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer. 2003;89(3):552–556. [PMC free article] [PubMed]
48. Moul JW, Srivastava S, McLeod DG. Molecular implications of the antiandrogen withdrawal syndrome. Semin Urol. 1995;13(2):157–163. [PubMed]
49. Knudsen KE, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res. 2009;15(15):4792–4798. [PMC free article] [PubMed]
50. Lassi K, Dawson NA. Update on castrate-resistant prostate cancer: 2010. Curr Opin Oncol. 2010;22(3):263–267. [PubMed]
51. Vasaitis T, Belosay A, Schayowitz A, et al. Androgen receptor inactivation contributes to antitumor efficacy of 17{α}-hydroxylase/17,20-lyase inhibitor 3β-hydroxy-17-(1H-benzimidazole-1-yl) androsta-5,16-diene in prostate cancer. Mol Cancer Ther. 2008;7(8):2348–2357. [PMC free article] [PubMed]
52. Handratta VD, Vasaitis TS, Njar VC, et al. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005;48(8):2972–2984. [PubMed]
53. Donovan MJ, Hamann S, Clayton M, et al. Systems pathology approach for the prediction of prostate cancer progression after radical prostatectomy. J Clin Oncol. 2008;26(24):3923–3929. [PubMed]
54. Cordon-Cardo C, Kotsianti A, Verbel DA, et al. Improved prediction of prostate cancer recurrence through systems pathology. J Clin Invest. 2007;117(7):1876–1883. [PMC free article] [PubMed]
55. Palmberg C, Koivisto P, Kakkola L, Tammela TL, Kallioniemi OP, Visakorpi T. Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer. J Urol. 2000;164(6):1992–1995. [PubMed]
56. Edwards J, Bartlett JM. The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 2: androgen-receptor cofactors and bypass pathways. BJU Int. 2005;95(9):1327–1335. [PubMed]
57. Niu Y, Altuwaijri S, Lai KP, et al. Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci USA. 2008;105(34):12182–12187. [PMC free article] [PubMed]
58. Culig Z, Stober J, Gast A, et al. Activation of two mutant androgen receptors from human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone. Cancer Detect Prev. 1996;20(1):68–75. [PubMed]
59. Culig Z, Hobisch A, Cronauer MV, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol. 1993;7(12):1541–1550. [PubMed]
60. Taplin ME, Rajeshkumar B, Halabi S, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol. 2003;21(14):2673–2678. [PubMed]
61. Marcelli M, Ittmann M, Mariani S, et al. Androgen receptor mutations in prostate cancer. Cancer Res. 2000;60(4):944–949. [PubMed]
62. Suzuki H, Sato N, Watabe Y, Masai M, Seino S, Shimazaki J. Androgen receptor gene mutations in human prostate cancer. J Steroid Biochem Mol Biol. 1993;46(6):759–765. [PubMed]
63. Wallen MJ, Linja M, Kaartinen K, Schleutker J, Visakorpi T. Androgen receptor gene mutations in hormone-refractory prostate cancer. J Pathol. 1999;189(4):559–563. [PubMed]
64. Taplin ME, Bubley GJ, Ko YJ, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 1999;59(11):2511–2515. [PubMed]
65. Gottlieb B, Beitel LK, Wu JH, Trifiro M. The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat. 2004;23(6):527–533. [PubMed]
66. Russell PJ, Bennett S, Stricker P. Growth factor involvement in progression of prostate cancer. Clin Chem. 1998;44(4):705–723. [PubMed]
67. Montgomery JS, Price DK, Figg WD. The androgen receptor gene and its influence on the development and progression of prostate cancer. J Pathol. 2001;195(2):138–146. [PubMed]
68. Matias PM, Donner P, Coelho R, et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem. 2000;275(34):26164–26171. [PubMed]
69. Sack JS, Kish KF, Wang C, et al. Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc Natl Acad Sci USA. 2001;98(9):4904–4909. [PMC free article] [PubMed]
70. Tilley WD, Buchanan G, Hickey TE, Bentel JM. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res. 1996;2(2):277–285. [PubMed]
71. Shi XB, Ma AH, Xia L, Kung HJ, de Vere White RW. Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res. 2002;62(5):1496–1502. [PubMed]
72. Ceraline J, Cruchant MD, Erdmann E, et al. Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer. Int J Cancer. 2004;108(1):152–157. [PubMed]
73. Jenster G, van der Korput HA, van Vroonhoven C, van der Kwast TH, Trapman J, Brinkmann AO. Domains of the human androgen receptor involved in steroid binding, transcriptional activation, and subcellular localization. Mol Endocrinol. 1991;5(10):1396–1404. [PubMed]
74. Gregory CW, He B, Johnson RT, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 2001;61(11):4315–4319. [PubMed]
75. Halkidou K, Gnanapragasam VJ, Mehta PB, et al. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene. 2003;22(16):2466–2477. [PubMed]
76. Agoulnik IU, Vaid A, Nakka M, et al. Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Res. 2006;66(21):10594–10602. [PubMed]
77. Heemers HV, Regan KM, Schmidt LJ, Anderson SK, Ballman KV, Tindall DJ. Androgen modulation of coregulator expression in prostate cancer cells. Mol Endocrinol. 2009;23(4):572–583. [PMC free article] [PubMed]
78. Gregory CW, Fei X, Ponguta LA, et al. Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. J Biol Chem. 2004;279(8):7119–7130. [PubMed]
79. Ueda T, Mawji NR, Bruchovsky N, Sadar MD. Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem. 2002;277(41):38087–38094. [PubMed]
80. Hobisch A, Eder IE, Putz T, et al. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res. 1998;58(20):4640–4645. [PubMed]
81. Krueckl SL, Sikes RA, Edlund NM, et al. Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model. Cancer Res. 2004;64(23):8620–8629. [PubMed]
82. George DJ, Halabi S, Shepard TF, et al. The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res. 2005;11(5):1815–1820. [PubMed]
83. Di Lorenzo G, Tortora G, D’Armiento FP, et al. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin Cancer Res. 2002;8(11):3438–3444. [PubMed]
84. Gioeli D, Ficarro SB, Kwiek JJ, et al. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem. 2002;277(32):29304–29314. [PubMed]
85. Craft N, Shostak Y, Carey M, Sawyers CL. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med. 1999;5(3):280–285. [PubMed]
86. Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C. From HER2/neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci USA. 1999;96(10):5458–5463. [PMC free article] [PubMed]
87. Ittmann MM. Chromosome 10 alterations in prostate adenocarcinoma (review) Oncol Rep. 1998;5(6):1329–1335. [PubMed]
88. Graff JR, Konicek BW, McNulty AM, et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem. 2000;275(32):24500–24505. [PubMed]
89. Lin HK, Yeh S, Kang HY, Chang C. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA. 2001;98(13):7200–7205. [PMC free article] [PubMed]
90. Wen Y, Hu MC, Makino K, et al. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 2000;60(24):6841–6845. [PubMed]
91. Bakin RE, Gioeli D, Sikes RA, Bissonette EA, Weber MJ. Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res. 2003;63(8):1981–1989. [PubMed]
92. McCall P, Gemmell LK, Mukherjee R, Bartlett JM, Edwards J. Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients. Br J Cancer. 2008;98(6):1094–1101. [PMC free article] [PubMed]
93. Guo Z, Dai B, Jiang T, et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 2006;10(4):309–319. [PubMed]
94. Kraus S, Gioeli D, Vomastek T, Gordon V, Weber MJ. Receptor for activated C kinase 1 (RACK1) and Src regulate the tyrosine phosphorylation and function of the androgen receptor. Cancer Res. 2006;66(22):11047–11054. [PubMed]
95. Mahajan NP, Liu Y, Majumder S, et al. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci USA. 2007;104(20):8438–8443. [PMC free article] [PubMed]
96. Mahajan K, Mahajan NP. Shepherding AKT and androgen receptor by Ack1 tyrosine kinase. J Cell Physiol. 2010 [PMC free article] [PubMed]
97. Tatarov O, Mitchell TJ, Seywright M, Leung HY, Brunton VG, Edwards J. SRC family kinase activity is up-regulated in hormone-refractory prostate cancer. Clin Cancer Res. 2009;15(10):3540–3549. [PubMed]
98. Attar RM, Takimoto CH, Gottardis MM. Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res. 2009;15(10):3251–3255. [PubMed]
99. Chi KN, Bjartell A, Dearnaley D, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment targets. Eur Urol. 2009;56(4):594–605. [PubMed]
100. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665–1671. [PubMed]
101. Labrie C, Simard J, Zhao HF, Belanger A, Pelletier G, Labrie F. Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate. Endocrinology. 1989;124(6):2745–2754. [PubMed]
102. Labrie F. Intracrinology. Mol Cell Endocrinol. 1991;78(3):C113–C118. [PubMed]
103. Dillard PR, Lin MF, Khan SA. Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol. 2008;295(1–2):115–120. [PMC free article] [PubMed]
104. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407–6415. [PubMed]
105. Geller J, Albert JD, Nachtsheim DA, Loza D. Comparison of prostatic cancer tissue dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy. J Urol. 1984;132(4):693–696. [PubMed]
106•• . Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653–4657. Demonstrates that intraprostatic dihydrotestosterone levels in castration-resistant prostate cancer patients remain at a level sufficient to activate AR signaling. [PubMed]
107. Mohler JL, Gregory CW, Ford OH, 3rd, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10(2):440–448. [PubMed]
108. Nishiyama T, Ikarashi T, Hashimoto Y, Wako K, Takahashi K. The change in the dihydrotestosterone level in the prostate before and after androgen deprivation therapy in connection with prostate cancer aggressiveness using the Gleason score. J Urol. 2007;178(4 Pt 1):1282–1288. [PubMed]
109. Nishiyama T, Hashimoto Y, Takahashi K. The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin Cancer Res. 2004;10(21):7121–7126. [PubMed]
110•• . Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815–2825. This study, for the first time, demonstrates increased expression of steroidogenic enzymes in prostate cancer tissues from castration-resistant prostate cancer patients. [PubMed]
111. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447–4454. [PMC free article] [PubMed]
112. Hofland J, van Weerden WM, Dits NF, et al. Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res. 2010;70(3):1256–1264. [PubMed]
113. Mostaghel EA, Montgomery B, Nelson PS. Castration-resistant prostate cancer: targeting androgen metabolic pathways in recurrent disease. Urol Oncol. 2009;27(3):251–257. [PMC free article] [PubMed]
114. Miller WL, Auchus RJ, Geller DH. The regulation of 17,20 lyase activity. Steroids. 1997;62(1):133–142. [PubMed]
115. Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer. 2009;100(5):671–675. [PMC free article] [PubMed]
116. Auchus RJ. Overview of dehydroepiandrosterone biosynthesis. Semin Reprod Med. 2004;22(4):281–288. [PubMed]
117. Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28(9):1496–1501. [PMC free article] [PubMed]
118. Chen Y, Sawyers CL, Scher HI. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol. 2008;8(4):440–448. [PMC free article] [PubMed]
119. Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004;351(15):1488–1490. [PubMed]
120. Bonkhoff H, Berges R. From pathogenesis to prevention of castration resistant prostate cancer. Prostate. 2010;70(1):100–112. [PubMed]
121. Fixemer T, Remberger K, Bonkhoff H. Apoptosis resistance of neuroendocrine phenotypes in prostatic adenocarcinoma. Prostate. 2002;53(2):118–123. [PubMed]
122. Bonkhoff H. Neuroendocrine differentiation in human prostate cancer. Morphogenesis, proliferation and androgen receptor status. Ann Oncol. 2001;12(Suppl 2):S141–S144. [PubMed]
123. Mitsiades CS, Bogdanos J, Karamanolakis D, Milathianakis C, Dimopoulos T, Koutsilieris M. Randomized controlled clinical trial of a combination of somatostatin analog and dexamethasone plus zoledronate vs. zoledronate in patients with androgen ablation-refractory prostate cancer. Anticancer Res. 2006;26(5B):3693–3700. [PubMed]
124. Koutsilieris M, Mitsiades CS, Bogdanos J, et al. Combination of somatostatin analog, dexamethasone, and standard androgen ablation therapy in stage D3 prostate cancer patients with bone metastases. Clin Cancer Res. 2004;10(13):4398–4405. [PubMed]
125. Koutsilieris M, Mitsiades C, Dimopoulos T, Ioannidis A, Ntounis A, Lambou T. A combination therapy of dexamethasone and somatostatin analog reintroduces objective clinical responses to LHRH analog in androgen ablation-refractory prostate cancer patients. J Clin Endocrinol Metab. 2001;86(12):5729–5736. [PubMed]
126. Colombel M, Symmans F, Gil S, et al. Detection of the apoptosis-suppressing oncoprotein bc1–2 in hormone-refractory human prostate cancers. Am J Pathol. 1993;143(2):390–400. [PMC free article] [PubMed]
127. McDonnell TJ, Troncoso P, Brisbay SM, et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992;52(24):6940–6944. [PubMed]
128. Furuya Y, Krajewski S, Epstein JI, Reed JC, Isaacs JT. Expression of bcl-2 and the progression of human and rodent prostatic cancers. Clin Cancer Res. 1996;2(2):389–398. [PubMed]
129. Gleave M, Tolcher A, Miyake H, et al. Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model. Clin Cancer Res. 1999;5(10):2891–2898. [PubMed]
130. De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7(4):256–269. [PMC free article] [PubMed]
131••. Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature. 2010;464(7286):302–305. Demonstrates the role of inflammation in the development of castration resistance. [PMC free article] [PubMed]
132. Nadiminty N, Lou W, Sun M, et al. Aberrant activation of the androgen receptor by NF-κB2/p52 in prostate cancer cells. Cancer Res. 2010;70(8):3309–3319. [PMC free article] [PubMed]
133. Khor LY, Bae K, Pollack A, et al. COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92–02 trial. Lancet Oncol. 2007;8(10):912–920. [PMC free article] [PubMed]
134. Di Silverio F, Sciarra A, Gentile V. Etoricoxib and intermittent androgen deprivation therapy in patients with biochemical progression after radical prostatectomy. Urology. 2008;71(5):947–951. [PubMed]


201. ClinicalTrials.Gov. Study of TAK-700 in combination with docetaxel and prednisone in men with metastatic castration-resistant prostate cancer. www.clinicaltrials.gov/ct2/show/NCT01084655.
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...