• 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;
Trends Endocrinol Metab. Author manuscript; available in PMC May 1, 2011.
Published in final edited form as:
PMCID: PMC2862880
NIHMSID: NIHMS177838

Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer

Abstract

Prostate cancer remains a leading cause of cancer death, as there are no durable means to treat advanced disease. Treatment of non-organ confined prostate cancer hinges on its androgen dependence. First line therapeutic strategies suppress androgen receptor (AR) activity, via androgen ablation and direct AR antagonists. While initially effective, incurable, "castration-resistant" tumors arise due to resurgent AR activity. Alterations of AR and/or associated regulatory networks are known to restore receptor activity and support resultant therapy-resistant tumor progression. However, recent evidence also reveals an unexpected contribution of AR ligand, wherein alterations in pathways controlling androgen synthesis support castrate-resistant AR activity. Herein, mechanisms underlying the lethal pairing of AR deregulation and aberrant androgen synthesis in prostate cancer progression will be discussed.

Keywords: Prostatic adenocarcinoma, androgen receptor, testosterone, 5α-dihydrotestosterone, PSA, review

Prostate cancer and AR addiction

To date, prostate cancer remains the second leading cause of cancer death and the most frequently diagnosed malignancy amongst men in the United States [1]. Locally confined prostate cancers can be effectively treated through either surgical resection or radiation therapy [2]. However, non-organ confined tumors represent a significant clinical challenge, accounting for significant morbidity. While the underlying mechanisms are not well understood, prostate cancers respond poorly to standard antimitotics used for chemotherapy. Thus, the first line of clinical intervention for patients with non-organ confined disease capitalizes on the established addiction of prostate cancers to androgen receptor (AR) signaling, and consists of a variety of mechanisms to ablate AR function [38]. These regimens are initially effective, resulting in AR activity suppression and tumor regression. However, incurable, “castration-resistant” cancers (CRPC, castration-resistant prostate cancers) develop in patients with disseminated disease within a median time of 2–3 years, wherein AR activity has been reactivated [4, 9]. Based on these clinical observations, there has been an intensive effort in the field to discern the mechanisms by which AR is reactivated in recurrent disease and to develop novel strategies to thwart this process.

AR regulation in prostate cancer

As a member of the steroid receptor subclass of nuclear receptors, AR functions as a ligand-dependent transcription factor (Figure 1) [4, 10]. In the absence of ligand (androgen) binding, the receptor is present diffusely throughout the cytoplasm and held in an inactive state in association with chaperones such as heat shock proteins (HSPs) [11]. While testosterone (T) is the most prevalent androgen present in sera of human males, it is converted into 5α-dihydrotestosterone (5α-DHT), a higher affinity ligand for AR, in prostatic epithelia or prostatic adenocarcinoma cells [12]. The Kd of T for AR=10−9 M while that of 5α-DHT for AR=10−11M. Ligand binding releases AR from HSPs, facilitating AR homodimerization, rapid nuclear translocation, post-translational modification, and receptor stabilization [11]. Activated AR dimers subsequently bind DNA at specific sequences deemed androgen responsive elements (AREs), serve as a platform for recruitment of coactivators and basal transcriptional machinery, and initiate a program of gene transcription that results in diverse biological outcomes dependent on cell context [1315]. To date, the best-characterized AR target gene is KLK3, which encodes the PSA (prostate specific antigen) protein. The ability to monitor PSA as a readout of AR function has had a major impact on diagnoses and management of human disease [16, 17]. As a serine protease secreted by the prostate, detection of serum PSA affords a facile mechanism through which to assess prostate-specific AR activity. As such, PSA screening is widely utilized to monitor disease development, tumor progression, and response to therapeutic intervention. Recent advances revealed that AR requires cooperating “pioneer” factors such as FoxA1 to enhance transcription, and that the predominant sites of AR action lie outside classical promoter regions of androgen responsive genes; in fact, AR function appears to be largely manifest through sites of action that lie in distal enhancers located in intragenic, intronic and intergenic regions [18, 19].

Figure 1
AR regulation in prostate cancer

While challenges exist for matching identified sites of AR binding to transcriptional output or disease relevance, several recent advances revealed the divergent function of AR in RPC. First, Wang et al. elegantly showed that in CRPC cells, AR occupies binding sites that overlap with but are distinct from those observed in tumor cells that are responsive to hormone ablation. Remarkably, AR appears to be enriched in castrate-resistant cells to regulate genes whose products control transitions into and through mitosis. One target gene of relevance, UBE2C, is required for castration-resistant cell growth, and is overexpressed in clinical CRPC specimens [18, 19]. Second, resurgent AR activity in VCaP xenograft models following castration promotes recurrent ERG expression from the TMPRSS2:ERG chromosomal translocation present within this model system [20]. Given the high frequency of TMPRSS2:ERG translocations in prostate cancer and the importance of ERG signaling for tumor phenotypes, these findings are of clinical significance. Most recently, two independent groups demonstrated that AR activation induces a close proximity of the TMPRSS2 and ERG chromosomal loci, and in the presence of ionizing radiation, actually promotes formation of the TMPRSS2-ERG chromosomal translocation [21, 22]. These striking findings present a model wherein AR activation binds chromatin to alter gene expression, but therein actively supports chromosomal aberrations. Combined, it is clear that the ability of AR to bind AREs and elicit a resultant gene expression program is critical for both early stage and castration-resistant disease, and these gene-expression profiles may be different.

AR as the primary therapeutic target for non-organ confined disease

The biochemical goal of first line intervention for non-confined tumors is to effectively suppress the transactivation potential of AR, regimens collectively referred to as androgen depletion or endocrine therapy [4, 5, 7]. GnRH agonists (e.g. leuprolide) represent the most frequently utilized means to deprive AR of ligand [7]. These drugs suppress the release of LH from the anterior pituitary and prevent Leydig cell testosterone biosynthesis in the non-castrate male. While these agents result in an initial spike of T release [23], testicular androgen synthesis is subsequently suppressed, resulting in serum T levels similar to those seen in surgically castrated men (<0.2 ng/mL) [24]. These strategies are sometimes used in combination with direct AR antagonists such as bicalutamide, which compete for agonist binding [4, 7]. In addition, the most commonly administered AR antagonists are thought to elicit conformational changes in the receptor that recruit corepressors (rather than coactivators) to sites of AR binding, thus assisting in active transcriptional repression [25]. That regimens are initially effective is incontrovertible; the vast majority of patients with disseminated disease show marked PSA declines (thus providing biochemical evidence of AR inactivation) and tumor remission [4, 7]. At the cellular level, hormone therapy results in both cell cycle arrest and cell death [15, 26]. However, recurrent tumor formation is common, and there remains no effective, durable means to treat this latter stage of disease [4, 7]. For CRPC, docetaxel shows modest efficacy in prolonging life but is not curative [27]. Development of detectable, recurrent tumors is almost invariably heralded by a preceding rise in serum PSA, thus indicating that AR is re-activated for disease progression [17]. Based on these observations and interrogation of AR function in models of human disease, it is widely accepted that AR is the key driver of prostate cancer progression and is required at all stages of disease for tumor maintenance [4, 7]. As such, it is of the utmost importance to fully delineate the mechanism(s) by which AR becomes reactivated in recurrent disease, and to discern the underlying pathways that impinge on this process.

AR reactivation in castrate-resistant disease

In the last decade, it has become quite clear that there are multiple mechanisms through which AR can be inappropriately reactivated in the presence of GnRH agonists (chemical castration) and direct AR antagonists. Means of AR reactivation in such castrate-resistant tumors can be loosely classified into mechanisms that: i) impinge directly on AR modulation; ii) involve alterations in AR cofactors, or iii) promote intratumor ligand synthesis (Figure 2). Each will be considered herein.

Figure 2
AR deregulation and CRPC development

Direct AR modulation

AR deregulation

Aberrant AR expression, alterations in upstream regulatory factors, and/or upregulation of required cofactors each significantly contributes to resurgent AR activity in CRPC. First, the great majority of CRPCs show marked induction of AR mRNA and protein expression [28, 29]. A fraction can be accounted for by amplification of the AR locus itself [3032], thus implicating genomic instability in CRPC. Little is understood about the additional mechanisms that promote enhanced AR expression. Loss of Pur-alpha, which can modulate the AR transcript through the 5’UTR, has been implicated in this process in model systems, but its clinical relevance remains uncertain [33]. Regardless of mechanism, it has been clearly demonstrated that deregulation of AR alone can have a major impact on prostate biology and therapeutic response. Transgenic animals wherein AR was modestly overexpressed in a prostate-specific manner showed evidence of both hyperplasia and carcinoma in situ, providing in vivo evidence for the pro-tumorigenic functions of AR overexpression [34]. Oncogenic transformation and progression to metastatic disease was observed in a transgenic model of prostate specific AR-E231G expression, thus validating the concept that AR gain-of-function mutations are sufficient to drive tumor development and progression [35]. In addition, analyses of xenograft models wherein hormone therapy-sensitive tumors progressed to recurrent tumors post-castration revealed that the major molecular change associated with CRPC was elevation of AR itself, reinforcing the hypothesis that disease progression is reliant on sustained AR signaling [36]. These same studies effectively demonstrated that AR induction alone is sufficient to bypass androgen depletion therapy and weaken the antagonist capabilities of bicalutamide. Collectively, these studies point to AR deregulation as a major mechanism of recurrent AR activity and CRPC formation.

AR mutation or alternative splicing

Alterations of AR also occur that can either significantly alter the spectrum of ligands that act as agonists or bypass the need for ligand altogether. A large number of somatic, tumor-derived mutations of AR have been identified, and the majority of these result in “promiscuous” ligand binding, facilitating activation of the receptor by non-androgen steroid hormones (e.g. progesterone, estrogens, cortisol and weak androgens [6, 9, 37]). A subset of these somatic mutations also convert known AR antagonists into agonists. Clinical situations referred to as “the anti-androgen withdrawal effect”, wherein cessation of therapies based on direct AR antagonism resulted in lower PSA levels, suggest that alterations in AR may change the cellular response to these therapeutically used receptor antagonists [38]. Indeed, a somatic mutation of AR identified in human disease, AR-T877A, results in flutamide-mediated receptor activation [39]. More recent studies identified mutations that result in receptor activation by bicalutamide [40]), and analyses of specimens from CRPC support the current hypothesis that specific AR antagonists select for development of specific AR somatic mutations [41]. Since the overall frequency and impact of somatic AR mutation in prostate cancer remains uncertain (and ranges from 8–25% in tumors analyzed), additional studies using relevant tissue (CRPC) are needed. In addition, it will be important to define the ligands that act as agonists for clinically relevant somatic mutants of AR. At present, it is clear that specific mutations are selected for during disease progression in a subset of tumors, resulting in increased ligand promiscuity and responsiveness, and active promotion of CRPC via non-androgens.

In addition, AR can be alternatively spliced in CRPC, resulting in receptors that decisively bypass the need for ligand [4244]. These “constitutively active” splice variants were first identified in prostate cancer cell lines, and shown to result in both cryptic exon usage and exon exclusion [4244]. While the precise number and frequency of the alternatively spliced variants remains to be rigorously determined, those identified to date retain the most critical transactivation domain of the receptor (AF1, located in the N-terminus) and the DNA binding domain, but are devoid of the ligand binding domain (LBD). It has been long appreciated that deletion of the LBD results in constitutively active AR [45], and revolutionary amongst these findings was the observation that LBD-deficient splice variants are enhanced in CRPC. Since these mutants would not be amenable to inhibition by LBD-directed AR antagonists (such as bicalutamide, TOK-001, or MDV3100), upregulation of such AR splice variants presents a significant clinical challenge. Combined, it is apparent that alterations in the AR coding region, either through somatic mutation or alternative splicing of the resultant transcript, play significant roles in human disease progression.

AR post-translational modifications

Recurrent AR activity can be achieved in the presence of hormone therapy through post-translational modification(s) that do not require alterations in the AR locus or mRNA processing. Not surprisingly, AR activity is modulated by disparate mechanisms that include serine/threonine phosphorylation, tyrosine phosphorylation, acetylation, ubiquitylation, and sumoylation [9, 46]. Some uncertainty remains with regard to the overall impact of individual modification events on subsequent modifications and total AR activity, but several key findings point to evidence for aberrant AR modification playing a role in human disease. For example, phosphorylated AR is associated with reduced survival in patients that have failed hormone therapy, thus implicating phosphorylation-derived AR modifications with disease progression [47]. Underlying mechanisms of aberrant phosphorylation events are emerging, and in many cases are attributed to growth factor receptor activation. Deregulated epidermal growth factor (EGF) activity can induce AR phosphorylation at Ser-578, resulting in castration-resistant receptor activity and tumor cell proliferation [48]. Other growth factors including IGF1 (recently reviewed in [49]) bolster AR activity in a low-ligand environment, supporting the contention that under certain conditions, peptide growth factors support overall AR activity. These findings are of potential disease relevance, as IGF1 is locally induced in human disease [50]. Conversely, tyrosine phosphorylation of AR appears to be predominantly driven by oncogene activation, especially via Src. This phosphorylation event is found with higher frequency in castrate-resistant tumors, and modeling of aberrant tyrosine phosphorylation supports the contention that deregulated tyrosine phosphorylation promotes ligand-independent AR activity and concomitant cellular proliferation [51]. Notably, EGF function is also partially dependent on Src-mediated AR tyrosine phosphorylation, supporting a role for multiple phosphorylation events in mediating growth factor-induced AR activation [51]. Intriguing new studies suggest that the tumor microenvironment may promote both events, as a neuroendocrine cell-derived protein (parathyroid hormone related protein, PTHrP) appears to promote EGF and Src-mediated AR modification and resultant adaptation to a low androgen environment [52]. Neuropeptides released by this cell type appear to serve similar functions [53]. Alternatively, AR phosphorylation can be enhanced through altered phosphatase activity. Recent reports indicate that PP1 associates with AR and regulates both receptor subcellular localization and stability [54]. These collective observations underscore the importance of external signals in modulating nuclear receptor function through phosphorylation cascades.

In addition to phosphorylation, AR is regulated by ubiquitylation, sumoylation, and acetylation events that may influence disease progression. The ubiquitin E3 ligase RNF6 promotes AR activity through selective modulation of cofactor recruitment (such as ARA54), and this function is enhanced in castrate-resistant tumors [55]. While similar observations were reported with TRIM68 [56], the Mdm2-mediated ubiquitylation of AR results in receptor destabilzation and loss of activity [57]. Thus, different ubiquitylation events appear to result in disparate effects on AR activity, and the underlying events that control these processes are incompletely understood. By contrast, conjugation of SUMO-1 to AR occurs rapidly after androgen binding, and cleavage of this process by SENP1 and SENP2 promotes gene-specific AR activation [58]. It has been suggested that this post-translational modification helps “fine tune” receptor activity. It will be of interest to determine how this process is regulated in human disease.

Alterations in AR cofactors

AR cofactors are cis-acting transcriptional modulatory proteins that substantially influence AR function. Given the prevailing posit that agonists induce recruitment of coactivators and antagonists promote conformational changes that promote recruitment of corepressors, two hypotheses emerge. First, it would be predicted that deregulation of coactivators or loss of corepressors promote unchecked AR activity and disease progression. Second, it is predicted that changes in overall AR levels alter the stoichiometry of assembled complexes. Both predictions appear to be correct and have disease relevance.

Coactivators

To date, several hundred putative AR coactivators have been identified that enhance ligand-dependent AR activity in model systems. These coactivators serve pleiotropic functions at the chromatin level, including recruitment of basal transcriptional machinery, modulation of chromatin remodeling enzymes function or recruitment (e.g. histone acetylase), and/or altered AR conformational changes. A subset of AR coactivators appear to be enhanced in human disease, including SRC1, SRC2, SRC3, or ARA70 [13, 5961]. The importance of deregulated coactivator expression may be significant, as excessive coactivator expression may not only sensitize cells to a low hormone environment but also convert nuclear receptor antagonists into partial or full agonists. As AR is known to regulate a distinct transcriptional program in hormone sensitive versus castrate-resistant models of disease [19], an attractive hypothesis is that altered cofactor expression and/or regulation assists in eliciting the CRPC-specific transcriptional program.

Corepressors

Loss of AR corepressor function can convert therapeutic antagonists into agonists or promote agonist sensitization (reviewed in [62]). Such events can occur through downregulation of the corepressor itself (such as occurs with prohibitin) [63, 64], through dismissal of the corepressor from the AR complex (as seen with NCoR in the presence of macrophage induced TAB2 signaling) [65], and/or through aberrant corepressor mislocalization (such as observed with Hey1) [66]. In addition to AR modulation, corepressors perturbed in prostate cancer may crosstalk with pathways directly associated with prostate cancer growth. For example, reduction of the AR corepressor Ebp1 is not only associated with resistance to hormone therapy, but also alters the proliferative response to heregulin [67]. Similarly, crosstalk between the AR and cell cycle machinery is mediated by cyclin D1, which acts through cyclin-dependent kinase-independent functions to suppress AR activity [15, 68]; this function of cyclin D1 is abrogated in human disease through downregulation, mislocalization, or alternative splicing events [15, 69]. As a result of such growth factor and cell cycle crosstalk functions embedded within selected AR cofactors, alterations therein may impinge both on AR signaling and connected pathways to yield a powerful pro-tumorigenic signal. Challenges remain with regard to discerning which of the several hundred co-repressors identified to date play critical roles in recurrent AR activity, and prioritizing those which could be developed as viable therapeutic targets.

Intratumor ligand synthesis

Most recently, it has become apparent that resurgent AR activity in CRPC can be accounted for in part through intratumoral androgen synthesis mediated by intracrine and paracrine mechanisms. As mentioned, prostate cancer is a disease whose growth is dependent on the male sex hormone T which is converted in the prostate by steroid 5α-reductase type 2 (SRD5A2) to yield the more potent androgen 5α-DHT [70] (Figure 3). Importantly, prostate cancer is a disease of the aging male and thus grows under the influence of androgens even as testicular output of T wanes. An alternative source of androgens in the aging male is the adrenal, whereby circulating dehydroepiandrosterone (DHEA) is converted in the prostate via the sequential actions of 3β-hydroxysteroid dehydrogenase [3β-HSD/ ketosteroid isomerase type 1 and type 2 (HSD3B1, HSD3B2), type 5 17β-HSD (AKR1C3)]; and 5α-reductase type 2 to yield 5α-DHT [7173]. In CRPC this intratumoral synthesis of androgens provides a mechanism by which the effects of a GnRH agonist on Leydig cell T synthesis can be surmounted. Indeed, increases in the androgenic synthetic pathway occur in CRPC as part of an adaptive response to androgen ablative therapy [7476].

Figure 3
Altered androgen biosynthesis and CRPC

The role of intratumoral synthesis in CRPC has been controversial since it did not adequately explain why AR receptor antagonists, e.g. flutamide and biaclutamide, failed and why early chemopreventive trials of finasteride (a selective 5α-reductase type 2 inhibitor) decreased prostate cancer incidence but resulted in the appearance of a more aggressive disease in some patients [77]. Proponents of the intratumoral synthesis of androgens point out that T and 5α-DHT are very potent hormones, and low concentrations might be sufficient to outcompete the effects of low affinity AR antagonists and activate AR [78]. In addition, the more aggressive tumors observed in the original finasteride prostate cancer chemopreventive trial are now widely accepted as being due to a sampling artifact due to the increased sensitivity of biopsies to detect cancer in the drug arm [79]. Studies on the use of finasteride to reduce intraprostatic 5α-DHT show that hormone levels are suppressed by only 68–86%, suggesting that other routes to this hormone exist [80]. Two routes to the synthesis of 5α-DHT that are independent of SRD5A2 are steroid 5α-reductase type 1 (SRD5A1) and “RoDH like 3α-HSD” (HSD17B6) [80, 81] (Figure 3). The latter enzyme catalyzes the back (oxidative) conversion of 3α-androstanediol to 5α-DHT. The recognition that two 5α-reductase isoforms are involved in intraprostatic synthesis of 5α-DHT has led to the development of dutasteride which inhibits both isoforms. Dutasteride is currently in clinical trial for the treatment and prevention of prostate cancer [80]. Earlier studies with dutasteride to treat benign prostatic hyperplasia indicated that it failed to reduce serum DHT levels altogether [82], and intraprostatic levels of DHT fell from 3.23 ng/g to 0.209 ng/g [83]. Alternatively, 5α-DHT can be formed by the “backdoor pathway” in which 3α-androstanediol is oxidized to 5α-DHT via RoDH-like 3α-HSD. In this pathway, Δ4-androstene-3,17-dione and testosterone are not precursors of 5α-DHT [84, 85]. This pathway starts with the conversion of pregnenolone to progesterone catalyzed by 3β-HSD2 (HSD3B2), formation of 17α-hydroxyprogesterone catalyzed by 17α-hydroxylase (CYP17A1), 5α-reduction to yield 5α-pregnane-17α-ol-3,20-dione (catalyzed by 5α-reductase isoforms), 3-ketone reduction to yield 5α-pregnane-3α,17α-diol-20-one (catalyzed by AKR1C2) followed by CYP-17,20-lyase (CYP17A1) to yield androsterone. Androsterone is then reduced to 3α-androstanediol by the action of AKR1C3. This “backdoor pathway” is thought to be important in the aging male when adrenal output of these steroids contributes more to prostate steroidogenesis. Thus far, “RoDH-like 3α-HSD” (17BHSD6) has not been targeted for androgen ablative therapy in prostate cancer since its role has only been recently elucidated.

The importance of intratumoral androgen synthesis following chemical or surgical castration has gained credence based on several observations. First, critical genes involved in androgen synthesis in the prostate are up-regulated at the transcript level in CRPC; these include HSD3B2 (1.8 fold increase); AKR1C3 (5.2 fold increase), SRD5A1 (2.1 fold increase); AKR1C2 (3.4 fold increase); and AKR1C1 (3.1 fold increase), where the latter two enzymes produce 3α-androstanediol and 3β-androstanediol, respectively from 5α-DHT [76] (Figure 3). These findings were observed in Affymetrix expression microarrays and validated by qRT-PCR [86]. In a separate study, the relative expression of the following transcripts changed in castrate-resistant metastases versus primary prostate tumors; CYP17A1 (16.9 fold increase) HSDD3B2 (7.5 fold increase) AKR1C3 (8.0-fold increase), SRD5A1 (2.6 fold increase) and SRD5A2 (9.4 fold decrease) [75]. Since these studies show that the ratio of AKR1C3:SRD5A2 transcripts increases, this may result in a decrease in the ratio of 5α-DHT:T within tumor samples. It was found that primary prostate tumors from eugonadal patients had a 5α-DHT:T ratio of 10:1, while this ratio was reversed to 0.25:1 in metastatic tumors [75]. Importantly, T levels measured by liquid chromatography-mass spectrometry in metastatic tumors are well within the range to stimulate AR, These studies suggest that in CRPC, the disease may become more dependent on T than 5α-DHT.

The second piece of evidence showing the importance of intratumoral androgen synthesis following chemical or surgical castration comes from xenograft studies. Using a LNCaP (an AR dependent prostate cancer cell line) mouse xenograft model for CRPC, increases in transcripts for androgen synthesizing enzymes were observed following extended castration and were coincident with increased PSA [87]. These studies suggest that during tumor reoccurrence, not only is there an increase in local androgen synthesis but this is sufficient to cause the induction of androgen sensitive genes. Importantly, there were additional changes in proteins responsible for the build up of free cholesterol and cholesterol synthesis (LDL-r, SR-B1, HMG-CoA reductase, StAR ACAT1, 2 and ABCA1) [88, 89] as well as changes in the expression of side-chain cleavage enzyme (CYP11A1) [87], suggesting that denovo steroidogenesis from cholesterol may take place in CRPC. Metabolism studies in the castrate resistant tumors provided evidence for denovo synthesis of 5α-DHT from [14C]-acetate [87]. In addition, metabolism studies with [3H]-progesterone provided evidence that intermediates in the backdoor pathway to 5α-DHT accumulate [74]. One caveat with these xenograft experiments is that in mice, CYP17A1 is not expressed in the adrenal, placing additional selection pressure on these tumors to synthesize their own androgens. However, the importance of this work is that even under conditions in which the mice are castrated and the adrenal is not producing DHEA, the tumors adapt to make their own androgens. These data indicate that following chemical or surgical castration, CRPC can be promoted by intratumoral androgen synthesis, and that denovo synthesis from cholesterol may also occur.

Third, abiraterone acetate (a CYP17α-hydroxylase/CYP17,20 lyase inhibitor), has shown important clinical response in individuals with CRPC leading to a reduction in bone metastases [90]. This response suggests that non-localized disease is still dependent on androgens, since this inhibitor blocks the conversion of either pregnenolone to DHEA or progesterone to Δ4-androstene-3,17-dione (Figure 3). This blockade could occur either in the adrenal or the prostate to prevent DHEA formation. Irrespective of where the blockade occurs, subsequent conversion of DHEA to T in the prostate is prevented. An important clinical outcome of abiraterone was a further decline in plasma T levels in CRPC by one log unit. Use of abiraterone acetate to treat CRPC can have the unintended consequence of inhibiting the conversion of pregnenolone to DHEA in the adrenal and lead to the diversion of pregnenolone into desoxycorticosterone which is a potent mineralocorticoid with glucocorticoid activity. To prevent the overproduction of desoxycorticosterone, abiraterone acetate is usually co-administered with dexamethasone to suppress the adrenal-pituitary axes and block ACTH formation [91]. Clearly, the effectiveness of abiraterone acetate has stimulated a reemergence of therapeutic approaches to block adaptive androgen synthesis in CRPC.

Fourth, in a recent small clinical study involving 10 patients, 80% showed slower progression of CRPC when they were given ketoconazole (a less selective CYP17α-hydroxylase/CYP17,20 lyase inhibitor than abiraterone acetate) in combination with dutasteride (Figure 3) [92]. A combination of agents that block androgen synthesis at multiple steps in CRPC could be a useful treatment strategy.

AKR1C3 is a prime therapeutic target downstream of CYP17α-hydroxylase/CYP17,20 lyase. This enzyme catalyzes the penultimate step in T biosynthesis in the prostate. Moreover, in metastatic disease we have seen that the ratio of 5α-DHT: T clearly favors T accumulation, suggesting that as the disease progresses, T may be the more dependent hormone [93]. These findings also raised the question whether AKR1C3 is the only reductive 17β-HSD expressed in prostate cancer. Type 3 17β-HSD (HSD17B3), also known as androgenic 17β-HSD catalyzes the conversion of Δ4-androstene-3,17-dione to testosterone in the Leydig cells, and was thought to be Leydig cell specific [94, 95]. Recently, evidence has emerged that this enzyme is also expressed in prostate cancer, but based on transcript levels AKR1C3 appears to be the dominant player [75]. Interestingly, AKR1C3 is potently and selectively inhibited by indomethacin suggesting that NSAID analogs that do not inhibit COX-1 or COX-2 might be effective agents for CRPC [96]. Taken together, it is apparent that alterations in androgen synthesis and androgen metabolism pathways are frequently observed in CRPC, presenting new opportunities for means to target AR activity and resultant tumor progression.

Conclusions and Future Directions

The studies described herein illustrate that deregulation of the mechanisms that control both AR activity and androgen levels promote disease progression and lethal tumor phenotypes. With this knowledge in hand, critical next steps and questions should be considered. First, how can the information be clinically translated? For example, if it is known that a patient harbors tumors with somatic mutations of AR, AR splice variants, or altered cofactor expression, is this information useful for directing treatment options? Second, are the mechanisms that underlie recurrent AR activity mutually exclusive? It is likely that different tumors display a repertoire of these mechanisms. Thus, molecular profiling of the tumor may ultimately have diagnostic and therapeutic value. In the future, a component of this molecular profiling must include sensitive and specific methods for measuring intratumoral androgen levels so that changes in the expression of androgen synthesizing genes can be validated at the functional level and enzymes targeted with specific inhibitors. Third, can more potent ligands be produced that suppress receptor function given the known mechanisms of androgen and AR deregulation? Recently, the darylthiohydantoins RD162 and MDV3100 were developed as more potent ligands for AR than bicalutamide. These compounds also reduce the efficiency of nuclear accumulation of AR, and impair binding to androgen response elements and coactivator recruitment. Of the first 30 patients with CRPC treated with MDV3100, 13/30 (43%) showed sustained declines in PSA [97]. There is also promise in designing single agents that could block androgen biosynthesis and AR function simultaneously. Analogs of abiraterone acetate e.g. 3-hydroxy-17-(1H-benzimidiazole-1-yl)androsta-5,16-diene, not only block CYP17α-hydroxylase/CYP17,20-lyase but are also potent anti-androgens and cause marked down-regulation of AR protein expression [98]. These agents are now entering clinical trial (TOK-001) and could be potentially important if CRPC is characterized by adaptive androgen synthesis and concurrent AR mutation to make the receptor more promiscuous to other ligands. Fourth, what mechanisms underlie the observed induction of enzymes that drive intratumor androgen synthesis? It will be important to determine the mechanisms by which these genes are induced and how their expression levels become permanently elevated. The promoters of the AKR1C1-AKR1C3 genes contain a number of half-sites for steroid hormone response elements. In addition, they all contain an anti-oxidant response element [99]. Whether inflammatory responses leading to reactive oxygen species generation to activate the antioxidant response element occurs remains an open question. Fifth, can AR cofactors or other critical effectors of ligand-bound receptor be developed as therapeutic targets? Advances in this area could provide new means to suppress AR activity, even in the presence of deregulated ligand synthesis.

In summary, it is clear that current means of therapeutic intervention for disseminated prostate cancer are circumvented in CRPC by both AR deregulation and aberrant androgen synthesis. This lethal pairing represents a major mechanism of tumor progression, and future efforts for development of new means to treat CRPC will need to consider both partners in crime.

Acknowledgements

This article was written with partial support from grants from the National Institutes of Health 1R01-CA90744 and P30-ES013508 awarded to TMP, CA116777 and CA099996 to KEK. The authors thank Dr. Steven Balk, Dr. Daniel Gioeli, Matthew Schiewer, and Sucharitha Balasubramaniam for critical commentary, and Elizabeth Gosnell for assistance with artwork. We regret omissions of related citations due to space constraints.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. [PubMed]
2. Klein EA, Ciezki J, Kupelian PA, Mahadevan A. Outcomes for intermediate risk prostate cancer: Are there advantages for surgery, external radiation, or brachytherapy? Urol Oncol. 2009;27:67–71. [PubMed]
3. Klotz L. Combined androgen blockade: an update. Urol Clin North Am. 2006;33:161–166. v–vi. [PubMed]
4. Knudsen KE, Scher HI. Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res. 2009;15:4792–4798. [PMC free article] [PubMed]
5. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25:1596–1605. [PubMed]
6. Taplin ME. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pract Oncol. 2007;4:236–244. [PubMed]
7. Chen Y, Sawyers CL, Scher HI. Targeting the androgen receptor pathway in prostate cancer. Curr Opin Pharmacol. 2008;8:440–448. [PMC free article] [PubMed]
8. Attar RM, Takimoto CH, Gottardis MM. Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res. 2009;15:3251–3255. [PubMed]
9. Yuan X, Balk SP. Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol. 2009;27:36–41. [PMC free article] [PubMed]
10. Claessens F, Denayer S, Van Tilborgh N, Kerkhofs S, Helsen C, Haelens A. Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nucl Recept Signal. 2008;6:e008. [PMC free article] [PubMed]
11. Centenera MM, Harris JM, Tilley WD, Butler LM. The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol Endocrinol. 2008;22:2373–2382. [PubMed]
12. Penning TM, Jin Y, Rizner TL, Bauman DR. Pre-receptor regulation of the androgen receptor. Mol Cell Endocrinol. 2008;281:1–8. [PMC free article] [PubMed]
13. 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;120:719–733. [PubMed]
14. Agoulnik IU, Weigel NL. Androgen receptor coactivators and prostate cancer. Adv Exp Med Biol. 2008;617:245–255. [PubMed]
15. Balk S, Knudsen K. AR, the cell cycle, and prostate cancer. Nuclear Receptor Signaling (NURSA) 2008;6:e001. [PMC free article] [PubMed]
16. Beekman KW, Hussain M. Hormonal approaches in prostate cancer: application in the contemporary prostate cancer patient. Urol Oncol. 2008;26:415–419. [PubMed]
17. Ryan CJ, Smith A, Lal P, et al. Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression. Urology. 2006;68:834–839. [PubMed]
18. Wang Q, Li W, Liu XS, et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell. 2007;27:380–392. [PMC free article] [PubMed]
19. Wang Q, Li W, Zhang Y, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell. 2009;138:245–256. [PMC free article] [PubMed]
20. Cai C, Wang H, Xu Y, Chen S, Balk SP. Reactivation of androgen receptor-regulated TMPRSS2:ERG gene expression in castration-resistant prostate cancer. Cancer Res. 2009;69:6027–6032. [PMC free article] [PubMed]
21. Lin C, Yang L, Tanasa B, et al. Nuclear Receptor-Induced Chromosomal Proximity and DNA Breaks Underlie Specific Translocations in Cancer. Cell. 2009;139:1069–1083. [PMC free article] [PubMed]
22. Mani RS, Tomlins SA, Callahan K, et al. Induced chromosomal proximity and gene fusions in prostate cancer. Science. 2009;326:1230. [PMC free article] [PubMed]
23. van Poppel H, Nilsson S. Testosterone surge: rationale for gonadotropin-releasing hormone blockers? Urology. 2008;71:1001–1006. [PubMed]
24. Oefelein MG. Time to normalization of serum testosterone after 3-month luteinizing hormone-releasing hormone agonist administered in the neoadjuvant setting: implications for dosing schedule and neoadjuvant study consideration. J Urol. 1998;160:1685–1688. [PubMed]
25. Shang Y, Myers M, Brown M. Formation of the androgen receptor transcription complex. Mol Cell. 2002;9:601–610. [PubMed]
26. Agus DB, Cordon-Cardo C, Fox W, et al. Prostate cancer cell cycle regulators: response to androgen withdrawal and development of androgen independence. J Natl Cancer Inst. 1999;91:1869–1876. [PubMed]
27. De Dosso S, Berthold DR. Docetaxel in the management of prostate cancer: current standard of care and future directions. Expert Opin Pharmacother. 2008;9:1969–1979. [PubMed]
28. 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;61:3550–3555. [PubMed]
29. Latil A, Bieche I, Vidaud D, et al. Evaluation of androgen, estrogen (ER alpha and ER beta), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Res. 2001;61:1919–1926. [PubMed]
30. 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;170:1817–1821. [PubMed]
31. Edwards J, Krishna NS, Grigor KM, Bartlett JM. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer. 2003;89:552–556. [PMC free article] [PubMed]
32. Brown RS, Edwards J, Dogan A, et al. Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer. J Pathol. 2002;198:237–244. [PubMed]
33. Wang LG, Johnson EM, Kinoshita Y, et al. Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex. Cancer Res. 2008;68:2678–2688. [PubMed]
34. Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP. Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proc Natl Acad Sci U S A. 2001;98:10823–10828. [PMC free article] [PubMed]
35. Han G, Buchanan G, Ittmann M, et al. Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci U S A. 2005;102:1151–1156. [PMC free article] [PubMed]
36. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–39. [PubMed]
37. Brooke GN, Bevan CL. The role of androgen receptor mutations in prostate cancer progression. Curr Genomics. 2009;10:18–25. [PMC free article] [PubMed]
38. Scher HI, Kelly WK. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol. 1993;11:1566–1572. [PubMed]
39. Middleman MN, Lush RM, Figg WD. The mutated androgen receptor and its implications for the treatment of metastatic carcinoma of the prostate. Pharmacotherapy. 1996;16:376–381. [PubMed]
40. Hara T, Miyazaki J, Araki H, et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003;63:149–153. [PubMed]
41. Steinkamp MP, O'Mahony OA, Brogley M, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res. 2009;69:4434–4442. [PMC free article] [PubMed]
42. 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;68:5469–5477. [PMC free article] [PubMed]
43. 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;69:16–22. [PMC free article] [PubMed]
44. 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;69:2305–2313. [PMC free article] [PubMed]
45. Jenster G, van der Korput HA, Trapman J, Brinkmann AO. Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem. 1995;270:7341–7346. [PubMed]
46. Faus H, Haendler B. Post-translational modifications of steroid receptors. Biomed Pharmacother. 2006;60:520–528. [PubMed]
47. 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;98:1094–1101. [PMC free article] [PubMed]
48. Ponguta LA, Gregory CW, French FS, Wilson EM. Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. J Biol Chem. 2008;283:20989–21001. [PMC free article] [PubMed]
49. Zhu ML, Kyprianou N. Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer. 2008;15:841–849. [PMC free article] [PubMed]
50. Chi KN, Bjartell A, Dearnaley D, et al. Castration-resistant Prostate Cancer: From New Pathophysiology to New Treatment Targets. Eur Urol. 2009;56:594–605. [PubMed]
51. Guo Z, Dai B, Jiang T, et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 2006;10:309–319. [PubMed]
52. DaSilva J, Gioeli D, Weber MJ, Parsons SJ. The neuroendocrine-derived peptide parathyroid hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen receptor. Cancer Res. 2009;69:7402–7411. [PMC free article] [PubMed]
53. Kung HJ, Evans CP. Oncogenic activation of androgen receptor. Urol Oncol. 2009;27:48–52. [PMC free article] [PubMed]
54. Chen S, Kesler CT, Paschal BM, Balk SP. Androgen receptor phosphorylation and activity are regulated by an association with protein phosphatase 1. J Biol Chem. 2009;284:25576–25584. [PMC free article] [PubMed]
55. Xu K, Shimelis H, Linn DE, et al. Regulation of androgen receptor transcriptional activity and specificity by RNF6-induced ubiquitination. Cancer Cell. 2009;15:270–282. [PMC free article] [PubMed]
56. Miyajima N, Maruyama S, Bohgaki M, et al. TRIM68 regulates ligand-dependent transcription of androgen receptor in prostate cancer cells. Cancer Res. 2008;68:3486–3494. [PubMed]
57. Gaughan L, Logan IR, Neal DE, Robson CN. Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation. Nucleic Acids Res. 2005;33:13–26. [PMC free article] [PubMed]
58. Kaikkonen S, Jaaskelainen T, Karvonen U, et al. SUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. Mol Endocrinol. 2009;23:292–307. [PubMed]
59. Xu J, Wu RC, O'Malley BW. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat Rev Cancer. 2009;9:615–630. [PMC free article] [PubMed]
60. Gregory CW, He B, Johnson RT, et al. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 2001;61:4315–4319. [PubMed]
61. Agoulnik IU, Vaid A, Bingman WE, 3rd, et al. Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression. Cancer Res. 2005;65:7959–7967. [PubMed]
62. Burd CJ, Morey LM, Knudsen KE. Androgen receptor corepressors and prostate cancer. Endocr Relat Cancer. 2006;13:979–994. [PubMed]
63. Dai Y, Ngo D, Jacob J, Forman LW, Faller DV. Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes. Carcinogenesis. 2008;29:1725–1733. [PMC free article] [PubMed]
64. Dart DA, Spencer-Dene B, Gamble S, Waxman J, Bevan C. Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours. Endocr Relat Cancer. 2009 [PMC free article] [PubMed]
65. Zhu P, Baek SH, Bourk EM, et al. Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell. 2006;124:615–629. [PubMed]
66. Belandia B, Powell SM, Garcia-Pedrero JM, Walker MM, Bevan CL, Parker MG. Hey1, a mediator of notch signaling, is an androgen receptor corepressor. Mol Cell Biol. 2005;25:1425–1436. [PMC free article] [PubMed]
67. Zhang Y, Linn D, Liu Z, et al. EBP1, an ErbB3-binding protein, is decreased in prostate cancer and implicated in hormone resistance. Mol Cancer Ther. 2008;7:3176–3186. [PMC free article] [PubMed]
68. Knudsen KE. The cyclin D1b splice variant: an old oncogene learns new tricks. Cell Div. 2006;1:15. [PMC free article] [PubMed]
69. Comstock CE, Augello MA, Benito RP, et al. Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer. Clin Cancer Res. 2009;15:5338–5349. [PMC free article] [PubMed]
70. Russell DW aW JD. Steroid 5α-reductase two genes/two enzymes. Ann Rev Biochem. 1994;63:25–61. [PubMed]
71. Labrie F, Belanger A, Simard J. Intracrinology. Autonomy and freedom of peripheral tissues. Annuals Endocrinology. 1995;56:23–29. [PubMed]
72. Labrie F, Luu-The V, Lin SX, Simard J, Labrie C, El-Alfy M, Pelletier G, Belanger A. Intracrinology: role of the family of 17β-hydroxysteroid dehydrogenases in human physiology and disease. J Mol Endocrinol. 2000;25:1–16. [PubMed]
73. Penning TM, Steckelbroeck S, Bauman DR, Miller MW, Peehl DM, Fung K-M, Lin HK. Aldo-keto reductase (AKR) 1C3: Role in prostate disease and the development of specific inhibitors. Mol Cell Endcorinol. 2006;248:182–191. [PubMed]
74. Locke J, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, Ettinger SI, Gleave ME, Nelson CC. Androgen levels increase by intratumoral de novo steroidogenesis during the progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407–6415. [PubMed]
75. Montgomery RBMEA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–4454. [PMC free article] [PubMed]
76. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815–2825. [PubMed]
77. Thompson I, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. The New England Journal of Medicine. 2003;349:215–224. [PubMed]
78. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smih-Jones PM, Yoo D, Kwon A, Wasieleska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second-generation antiandrogen for the treatment of advanced prostate cancer. Science. 2009;324:787–790. [PMC free article] [PubMed]
79. Redman M, Tangen CM, Goomdan PJ, Luica MS, Coltman CA, Jr, Thompson IM. Finasteride does not incresae the risk of high-grade prostate cancer: a bias-adjusted modeling approach. Cancer Prev Res. 2008;1:174–181. [PMC free article] [PubMed]
80. Rittmaster RS. 5a-Reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction. Best Practice & Research Clinical Endocrinol & Metab. 2008;22:389–402. [PubMed]
81. Bauman DR, Steckelbroeck S, Williams MV, Peehl DM, Penning TM. Identification of the major oxidative 3α-hydroxysteroid dehydrogenase in human prostate that converts 5α-androstane-3α,17β-diol to 5α-dihydrotestosterone: A potential therapeutic target for androgen dependent disease. Mol Endocrinol. 2006;20:444–458. [PubMed]
82. Nickel JC. Comparison of clinical trials with finasteride and dutasteride. Rev Urol. 2004;6 Suppl 9:S31–S39. [PMC free article] [PubMed]
83. Wurzel R, Ray P, Major-Walker K, Shannon J, Rittmaster R. The effect of dutasteride on intraprostatic dihydrotestosterone concentrations in men with benign prostatic hyperplasia. Prostate Cancer Prostatic Dis. 2007;10:149–154. [PubMed]
84. Auchus R. The backdoor pathway to dihydrotestosterone. Trends in Endocrinol & Metab. 2004;15:432–438. [PubMed]
85. Penning TMBD, Jin Y, Rizner TL. Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor. Mol Cell Endocrinol. 2007;265–266:77–82. [PMC free article] [PubMed]
86. 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;66:2815–2825. [PubMed]
87. 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;68:6407–6415. [PubMed]
88. Leon CG, Locke JA, Adomat HH, et al. Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model. Prostate. 2009 [PubMed]
89. Locke JA, Guns ES, Lehman ML, et al. Arachidonic acid activation of intratumoral steroid synthesis during prostate cancer progression to castration resistance. Prostate. 2009 [PubMed]
90. Attard GRA, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS. 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;26:4563–4571. [PubMed]
91. 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;26:4563–4571. [PubMed]
92. Sartor O, Nakabayashi M, Taplin ME, Ross RW, Kantoff PW, Balk SP, Oh WK. Activity of dutasteride plus ketoconazole in csatration-refratry prostate cancer after progression on ketoconazole alone. Clin Genitourin Cancer. 2009;7:E90–E92. [PubMed]
93. 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;68:4447–4454. [PMC free article] [PubMed]
94. Andersson S, Geissler WM, Patel S, Wu L. The molecular biology of androgenic 17β-hydroxysteroid dehydrogenases. J Steroid Biochem Mol Biol. 1995;53:37–39. [PubMed]
95. Andersson SGWM, Wu L, Davis DL, Grumbach MM, New MI, Schwarz HP, Blethen SL, Mendonca BB, Bloise W, Witchel SF, Cutler GB, Jr, Griffin JE, Wilson JD, Russell DW. Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab. 1996;81:130–136. [PubMed]
96. Byrns MCSS, Penning TM. An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies. Biochem Pharmacol. 2008;75:484–493. [PMC free article] [PubMed]
97. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–790. [PMC free article] [PubMed]
98. Vasaitis TBA, Schayowitz A, Khandelwal A, Chopra P, Gediya LK, Guo Z, Fang HB, Njar VC, Brodie AM. Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther. 2008;7:2348–2357. [PMC free article] [PubMed]
99. Penning TaD JE. Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphism. Arch Biochem Biophys. 2007;464:241–250. [PMC free article] [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...