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Molecular Biology of the Androgen Receptor

From the Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, 3800 Reservoir Rd NW, Washington, DC.

Address reprint requests to Edward P. Gelmann, MD, Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, 3800 Reservoir Rd NW, Washington, DC 20007-2197; email: gelmanne{at}georgetown.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION REFERENCES

 
ABSTRACT: Androgen receptor (AR) is a member of the steroid hormone receptor family of molecules. AR primarily is responsible for mediating the physiologic effects of androgens by binding to specific DNA sequences that influence transcription of androgen-responsive genes. The three-dimensional structure of the AR ligand-binding domain has shown it is similar to other steroid hormone receptors and that ligand binding alters the protein conformation to allow binding of coactivator molecules that amplify the hormone signal and mediate transcriptional initiation. However, AR also undergoes intramolecular interactions that regulate its interactions with coactivators and influence its activity. A large number of naturally occurring mutations of the human AR gene have provided important information about AR molecular structure and intermolecular interactions. AR is also a critical mediator of prostate cancer promotion, conferring growth signals to prostate cancer cells throughout the natural history of the disease. Late-stage prostate cancer, unresponsive to hormonal deprivation, sustains AR signaling through a diverse array of molecular strategies. Variations in the AR gene may also confer genetic predisposition to prostate cancer development and severity. Further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION REFERENCES

 
ONE ONLY HAS TO compare even very young children to imagine that the effects of the androgen receptor (AR) have broad developmental and psychologic effects even at the earliest stages of life. Moreover, AR has important effects throughout life, ranging from the obvious effects on pubertal development to the physiologic dysregulation that contributes to male pattern baldness, to the genesis of prostatic hyperplasia, and later in life to prostate cancer. The diverse effects of AR are mediated by complex cell type-specific signaling pathways. During the past several years, there have been a number of new insights into the mechanism of AR action in normal cells. Detailed molecular genetic analyses elucidating the functional domains of the AR molecule and the deciphering of the three-dimensional crystal structure of the ligand-binding domain (LBD) have both markedly expanded our understanding of AR molecular physiology. Moreover, research into the molecular pathology of prostate cancer has shown that the AR gene is a target for mutation or amplification in prostate cancer cells and therefore plays a critical role in the pathogenesis and tumor progression of this very common cancer. This review will attempt to place these new findings into context, provide an overview of our current understanding of AR structure, and describe current understanding of its role in prostate cancer. Other reviews on AR, its coactivators, physiology, endocrinology, and its role in prostate cancer should also be consulted.^1-10

The AR gene is located on the X chromosome and therefore is single-copy in males, which allows for the phenotypic manifestation of mutations without the influence of a wild-type codominant allele. Medical geneticists have cataloged more spontaneous mutations of human AR than of any other gene in part because AR is not essential to the formation of a viable human organism. Descriptions of the structure-function relationships of these mutations have shed important light on functional domains of the AR molecule. Complete loss of AR function in genetic (XY) males results in the complete androgen insensitivity syndrome manifest as phenotypic, though sterile, females who, significantly, are accepting of their sex identity.¹¹ This suggests that AR is a critical developmental trigger not only for male morphologic development but also for configuration of the male CNS. Missense mutations that attenuate AR activity are responsible for partial androgen insensitivity syndrome. For a comprehensive review of the developmental impact of AR and of the androgen insensitivity syndromes, the reader is referred to the article by Quigley et al.⁷

AR GENE CHROMOSOMAL LOCATION AND GENE STRUCTURE
The AR gene is located on chromosome Xq11-12.^12,13 The gene is oriented with the 5' end toward the centromere and spans 90 kb of DNA containing eight exons that code for a 2,757-base pair open reading frame within a 10.6-kb mRNA^14-17 (Fig 1). AR is a member of the steroid hormone receptor family of genes. Like the other members of this family of transcription factors, the exons of the AR gene code for functionally distinct regions of the protein similar to the modular structure of other steroid hormone receptor genes. The AR genomic organization is conserved throughout mammalian evolution from rodents to man. Indeed, the location of AR on the X chromosome is preserved in other animals, such as marsupials and monotremes, and may reflect a developmentally significant association of AR with other syntenic genes.¹⁸ The first exon codes for the N-terminal domain (NTD) that is the transcriptional regulatory region of the protein. Exons 2 and 3 code for the central DNA-binding domain (DBD). Exons 4 to 8 code for the C-terminal LBD.

View larger version (31K): [in this window] [in a new window]   Fig 1. Genomic organization of the AR gene is shown. The genome spans more than 80 kb that includes the exonic organization shown in the second panel. Location of three codon repeat regions in the first exon that codes for the N-terminal domain is shown in the third panel. The diagram of the protein structure demonstrates how the exon organization translates into discrete functional regions of the receptor. Adapted from Quigley et al.7

The presence of a CAG triplet repeat places the AR in the category of genes for which excessive extension of the CAG repeat can result in an inherited neuromuscular degenerative disease. Kennedy’s disease or spinal and bulbar muscular atrophy is caused by extension of the AR CAG repeat length to 40 to 62 repeats.¹⁹ Individuals with Kennedy’s disease develop progressive neurologic impairment caused by degeneration of spinal motor neurons and muscle wasting in the fourth through sixth decades of life. The neurologic manifestations of Kennedy’s disease are due to the fact that proteins containing excessively long polyglutamine stretches induce neuronal cell apoptosis, an important pathogenic mechanism in some neurodegenerative diseases.^23-26 Further confirmation for the pathogenesis of Kennedy’s disease comes from the appearance of neurodegenerative disease in mice expressing an AR transgene with expanded CAG repeat.²⁷ Interestingly, Kennedy’s disease is also accompanied by androgen insensitivity caused by attenuated activity of the AR with a long poly-Q region in the NTD.¹⁹

AR TRANSCRIPTION
Transcription of the AR gene is cell-type specific and also age-specific in some tissues. Moreover, AR mRNA levels are regulated by androgen and by other steroid hormones. The promoter region of the AR gene lacks typical TATA and CAAT sequences in the region immediately 5' to the start of the mRNA. As is not uncommon with TATA-less genes, the 5' untranslated region of the gene contains GC-rich sequences that bind the transcription factor SP1.^17,28 The AR gene is transcribed from at least two separate promoter start sites whose activities vary depending on cell type.²⁹ Studies of the rat AR gene promoter have identified binding sites for a wide range of transcriptional activators.²⁸ Consistent with its widespread effects, AR is expressed in cells of a wide range of tissues far beyond primary and secondary sexual organs. In fact, except for the spleen, it is difficult to find a tissue that does not express some amount of AR (reviewed in^7,10). Not only is there tissue-specific control of AR transcription but also age-dependent variations that have been observed in rat liver that is mediated by transcription factor binding to specific target sequences in the promoter.^30,31

The rat AR promoter also contains palindromic DNA binding sites recognized by the AR, the glucocorticoid receptor, and the progesterone receptor.^28,32 AR action is regulated to some degree by negative feedback to transcription of the AR gene itself. Castration results in increased AR mRNA that is reversed by administration of androgen.^33,34 Rat AR expression is downregulated by androgen and by the gonadotropin follicle-stimulating hormone, which may act by inducing cyclic AMP for which the AR promoter contains a response element.^35-38

EVOLUTIONARY CONSERVATION OF AR
Conservation of segments of the AR gene throughout evolution implicates these regions as being critical for the activity of the molecule. The DBD is most highly conserved from Xenopus to human, and the LBD is also highly conserved. Other regions of the gene that retain a striking concentration of sequence conservation include much of the hinge region and the LBD.³⁹ Consistent with the biologic requirement that the AR molecule bind its cognate ligand, 12 of the 43 conserved codons of the LBD map to the coding region for the ligand-binding pocket. A large number of LBD sites that are targets for mutation resulting in androgen insensitivity syndrome are conserved from frog to man. In addition, the hinge region, particularly its N-terminal domain, is also highly conserved from frog to rodent.³⁹ The NTD, encoded by the first exon, displays virtually no conservation from frog to rodent to man upstream from codon 539 in the human sequence. However, sequence comparison of NTDs from primates reveals that codons 1 to 53 and 360 to 429 generate conserved protein segments across a broad evolutionary spectrum.⁴⁰ These regions are important for dimerization of human AR and their genetic conservation reflects functional similarity for all primate AR molecules.

AR PROTEIN STRUCTURE AND ACTIVITY
LBD During the last 2 years, the three-dimensional structure of the AR LBD has been determined.^41,42 The AR LBD structure has now been added to the catalog of steroid hormone receptor family members whose LBDs have been analyzed crystallographically. Among these are estrogen receptors alpha and beta,^43-45 progesterone receptor, vitamin D receptor, retinoic acid receptors RXR and RAR-alpha, thyroid hormone receptors, and peroxisome proliferator-activating receptors.⁴⁶ Despite substantial differences in the primary amino acid sequence between the AR LBD and other steroid hormone receptors, in some cases as low as 20% similarity, the three-dimensional structures of the LBDs of these molecules are quite similar. The LBDs of these receptors fold into 12 helices that form a ligand-binding pocket (Fig 2A). When an agonist is bound, for example, to the estrogen receptor, helix 12 folds over the pocket to enclose the ligand. When an antagonist is unbound, helix 12 is positioned away from the pocket in a way that interferes with the binding of coactivators to a groove in the hormone-binding domain formed after ligand binding.⁴³ In AR, ligand binding that induces folding of helix 12 to overlie the pocket discloses a groove that binds a region of the NTD. Coactivator molecules can also bind to this groove, but the predominant site for coactivator binding to AR is in the NTD.^47,48 AR ligand resides in a pocket and primarily contacts Q711, M745, and R752 at the A ring of the steroid backbone and L704 and N705 at the C ring. Thus helices 4, 5, and 10 are the primary AR contact regions for ligand binding (Fig 2B).

View larger version (31K): [in this window] [in a new window]   Fig 2. Three-dimensional structure of the AR LBD. (A) A ribbon diagram of the AR LBD is shown with the ligand in the binding pocket. The 12 helices are numbered as are the N and C termini of the LBD, Note that the ligand-binding pocket is formed by helices 3, 5, and 10. (Reprinted and modified from Sack et al42 by permission from the publisher.) (B) Detailed view of the AR ligand-binding pocket. Note that T877, the site of the LNCaP and many prostate cancer mutations, makes direct contact with the ligand. Alternation of 877 or other amino acids shown result in conformational changes in the binding pocket that broaden the scope of molecules that can be accommodated. (Revised by Stanley R. Krystek, Bristol-Myers Squibb, from a figure in Sack et al.42 Printed with permission of the publisher.) (C) Three-dimensional structure of the AR LBD with pathogenic mutations. The colored spheres indicated the location of mutations that affect the LBD in prostate cancer and androgen insufficiency syndromes. Mutations observed in prostate cancer are represented in red; those observed for CAIS are shown in yellow, and those observed for PAIS/MAIS are in cyan. Mutation of one residue (M749) is implicated in both prostate cancer and CAIS and is represented in orange. (Figure and part of the legend reprinted by permission from Matias et al.41)

DBD The DBD includes 70 amino acids that are encoded by exons 2 and 3 and is the region best conserved among the steroid hormone receptors. The DBD amino acid sequence of human AR is 100% identical to rat AR. Among other human steroid hormone receptors, the AR DBD is 79% identical to progesterone receptor, 76% identical to glucocorticoid receptor, and 56% identical to estrogen receptor-alpha. The DNA-binding region includes eight cysteine residues that form two coordination complexes, each composed of four cysteines and a Zn²⁺ ion. These two zinc fingers form the structure that binds to the major groove of DNA⁴⁹ (Fig 3). Assuming that AR DNA binding behaves identically to glucocorticoid receptor, K580 and R585 in the first zinc finger bind, respectively, to the second and fifth nucleotide pairs in the first androgen-response element (ARE) repeat GGTACA.^50-54

View larger version (24K): [in this window] [in a new window]   Fig 3. Amino acid sequence of the AR DBD showing the formation of two zinc fingers that are each configured due to binding of four cysteine residues to a zinc ion. Three residues in boxes, G, S, and V, are highly conserved among steroid hormone receptors such as progesterone and glucocorticoid receptor and are the sites of contact with the ARE. The nuclear localization signal sequence (NL in circle) is C-terminal to the DBD. (Adapted from Hiipakka and Liao189 and printed by permission of the publisher.)

The ARE in DNA is composed of two palindromic hexanucleotide half sites separated by a three-nucleotide spacer.⁵³ There is substantial variation between the AREs seen in different promoter regions. However, single nucleotide differences in AREs affect the affinity of different receptors for DNA and can influence the relative effects of different steroid hormone receptors on specific promoter regions.⁵⁷ In addition, the presence of multiple AREs in a promoter region causes tandem promoter binding and enhancement of AR specificity and action.^58-60 In fact, individual AREs in general have low activity in in vitro assays of transcription. Androgen-induced transcriptional activity that mimics transcriptional activation seen in cells requires the presence of a number of AREs arranged in the correct spatial orientation.^61-63 Therefore, specificity for hormone action must be dictated to some extent by other regions of the receptor and interaction with other cis-acting elements that participate in transcriptional initiation.^64,65 Moreover, there are two classes of ARE that cooperate to enhance AR binding to DNA and may be critical for determining specificity of hormonal responsiveness of a promoter. AR will bind to guanine residues indicated by underlined letters in the sequence RGAACA-NGN-TGTNCT. AR will also bind to a second class of ARE, RGGACA-NNA-AGCCAA, that mediates cooperation between adjacent bound receptors and enhances the specificity of androgen responsiveness.⁶⁶

NTD The NTD is the primary effector region of AR and is largely responsible for transactivation. Deletion of the LBD from the AR results in a residual N-terminal fragment with constitutive activity nearly equal to the transcriptional activity of the ligand-bound, full-length protein. This differs from other steroid hormone receptors whose activity is attenuated by deletion of the C-terminal LBD and suggests that the primary site for interaction of AR with coactivator molecules that amplify the transcriptional signal and mediate AR action is via the NTD. The NTD is the region of AR with the least evolutionary conservation. There is only 20% amino acid identity between human and rat NTD. Therefore, it is not surprising that this region has some functional characteristics that are unique compared with other members of the steroid hormone receptor family. The first 140 amino acids are not essential for transcriptional activity. Their deletion results in a receptor with nearly wild-type levels of activity. However, deletion of regions further downstream, between amino acids 210 and 337, markedly reduce receptor activity.⁶⁷ In studies of intramolecular AR interactions, it was shown that amino acids 142 to 337 were not required for receptor dimerization. However, deletions of 14 to 150 reduced and of 339 to 499 eliminated regions that mediate interaction with the LBD.^68-70 Further discussion of the NTD follows in the next section.

MOLECULAR MECHANISMS OF AR ACTION
Before ligand binding, many steroid hormone receptors reside in the cytoplasm, where they are sequestered by binding to chaperone molecules such as heat shock proteins. The entry of ligands into the cell results in receptor binding causing a conformational change that releases heat shock proteins and allows the steroid hormone receptor to be translocated to the nucleus.^71-76 Although studies with AR in some experimental systems suggest that before ligand binding the receptor is cytoplasmic, it is possible that endogenous AR may in fact reside largely in the nucleus (E. Wilson, personal communication, September 2001). Subcellular localization of AR may also be cell-type specific.^77,78 Nuclear targeting of AR is influenced by the hinge region, where a deletion markedly reduces ligand-induced nuclear translocation but does not totally block signaling.^67,79 AR also contains two basic nuclear targeting regions similar to nucleoplasmin, a histone-binding protein.⁷⁷

Regulation of steroid hormone receptor action occurs, in part, by posttranslational modification, such as phosphorylation.⁸⁰ Phosphorylation of steroid hormone receptors occurs under different conditions and for apparently different reasons depending on the receptor. For example, phosphorylation of progesterone receptor is both hormone-dependent and important for transcriptional activation.^81,82 On the other hand, there are multiple phosphorylation sites on glucocorticoid receptor, none of which seem to be necessary for receptor activity. AR is phosphorylated on at least three sites, S81, S94, and S650. The first two were not important for AR activity in some experimental systems, but their physiologic role has not been determined. AR is phosphorylated at a number of sites in response to agonist binding that result in nuclear localization, but usually not in response to antagonists.^83-85 Recently, it was shown that S81 phosphorylation is regulated in response to steroid hormones and S650 in response to forskolin and phorbol ester, which implies a regulatory role for S650 phosphorylation in signal transduction mediated by cyclic AMP and protein kinase C (D.G. Gioeli and M.J. Weber, personal communication, September 2001). In contrast to the other phosphorylation sites, the S650 site in the hinge region is required for full AR transcriptional activity.⁸⁶ Serine 308 has also been shown to be a target for phosphorylation, although its physiologic role is unknown.⁸⁷

Even in the cytoplasm, before nuclear translocation, ligand-bound steroid hormone receptors have biologic effects. Both AR and estrogen receptor can bind to homologous or heterologous ligands in the cytoplasm and exert inhibitory effects on cell death processes.⁸⁸ However, these effects are of relatively low magnitude compared with the profound effects on cell growth, survival, and differentiation that occur when ligand-bound steroid hormone receptors enter the nucleus.⁸⁹ Ligand-bound steroid hormone receptors bind to specific DNA sequences and initiate the formation of a protein complex at the promoter region of hormone-responsive genes that initiates transcription.⁹⁰ Whereas several steroid hormone receptors have been observed to form homodimers in solution and in crystal structure,⁹¹ AR has not been observed to form a homodimer in vitro in the absence of a DNA-binding sequence.^42,92

The binding of steroid hormone receptors to DNA is the first step in the assembly of a protein complex on the DNA that amplifies the signal initiated by steroid hormone receptor binding. Steroid hormone receptor action is mediated by a family of coactivator proteins that amplify the signal, mediate CREB-binding protein recruitment to the receptor complex, and initiate RNA polymerase activity.⁹³ Steroid hormone receptor action is attenuated by the binding of corepressor molecules that inhibit transcriptional initiation.⁹⁴ The binding of corepressor molecules is favored when antihormones occupy the ligand-binding pocket.^95,96 AR triggers assembly of activated transcriptional complexes at an ARE in response to dihydrotestosterone binding, but complexes with the corepressor NCOR when bound to antiandrogens like bicalutamide. The proximity of enhancer elements in the DNA sequence can form additional transcription complexes that align with the primary promoter complex and amplify the formation of a transcriptional complex.⁹⁷

The binding of p160 coactivators to steroid hormone receptors occurs at a specific groove that is created by the apposition of helices 3, 4, 5, and 12 that is formed after ligand binding.^43,98-101 This groove is revealed when helix 12 is positioned over the ligand-binding pocket occupied by a receptor agonist. Helix 12 is displaced from a ligand-binding pocket that contains a receptor antagonist such that helix 12 interferes with coactivator binding. For this reason helices 3, 4, 5, and 12 are the sites of activating factor (AF)-2 activity that was discovered by mutational analysis to be important for p160 coactivator binding.⁴³ Coactivator molecules contain a consensus peptide of the motif LXXLL (L is leucine and X is any amino acid) in a region called the NR box, which binds to the groove in steroid hormone receptors.^93,102 Many of these proteins belong to the steroid receptor coactivator family and bind to the AF-2 region in the C terminus of ligand-bound receptors such as the estrogen receptor. Other proteins, such as CREB-binding protein, complex with AR near the DBD to participate in a multiprotein transcriptional complex.^90,94,103 Hormone-dependent binding of p160 coactivators through the LXXLL motifs results in the activation of histone acetyltransferase activity, which plays a role in chromatin remodeling to allow for active transcription of DNA.^104,105

Whereas estrogen and thyroid hormone receptors, for example, interact with coactivators via contact points in the LBD, AR interaction with coactivators occurs primarily via regions of the NTD.¹⁰⁶ Moreover, coactivators interact with the AR NTD via a glutamine-rich region rather than via the LXXLL NR box motif that mediates interaction with estrogen receptor.⁴⁷ Although coactivator LXXLL motifs may interact with the AR LBD, the AR AF-2 domain seems to be the preferred C-terminal site for interaction with the AR NTD. Interaction between the NTD and LBD of the ligand-bound receptor is essential for AR activity.^{68-70,107-110}

Helix 12 of ligand-bound AR is stabilized by interaction with either of two regions in the AR NTD.¹⁰⁶ This interaction facilitates binding of p160 coactivators to AR in a manner that is independent of the LXXLL NR boxes. Moreover, the interaction of N-terminal and AF-2 domains stabilizes receptor-ligand interactions and is required for ligand-dependent activation of the receptor. In fact, two pentapeptide regions of the AR N terminus, ²³FQNLF²⁷ (FXXLF) and ⁴³³WHTLF⁴³⁷ (WXXLF), mediate binding of the N terminus to the C-terminal region of AR. ²³FQNLF²⁷ interacts with the AF-2 groove formed by helices 3, 4, 5, and 12 and competes favorably with LXXLL-containing coactivator proteins for ligand-dependent binding to the LBD.¹¹¹ The interaction of ligand-bound AR with coactivators is still not wholly understood, since some coactivators interfere with N/C interactions and others enhance those same interactions.¹⁰⁸ The pentapeptide ⁴³³WHTLF⁴³⁷ also binds to the C-terminal region but at a site outside the AF-2 groove. It may be that this interaction follows ligand binding and is facilitated by interaction between ²³FQNLF²⁷ and AF-2 so as to strengthen interactions between AR NTD and LBD.¹¹² In fact, coactivators may be favored for AR binding because of FXXLF pentapeptides that compete favorably with the AR NTD for AF-2.¹¹³

The importance of both NTD and LBD for AR activity is underscored by spontaneous mutations in these regions that cause either complete or partial androgen insensitivity. The importance of NTD-LBD interactions are underscored by the fact that complete androgen insensitivity syndrome can be caused by missense mutations in helix 12 and in other regions of the LBD that interact with the NTD.⁷ Even though the mechanism of interaction between AR and coactivators may differ from that of other steroid hormone receptors, coactivators are still essential for AR action in vivo. This is underscored by the observation that androgen insensitivity syndrome occurred in an individual with a mutation in a coactivator gene and a normal AR gene.¹¹⁴

AR AND PROSTATE CANCER RISK
The prostate gland depends on androgens for its development and maintenance of its integrity. Congenital AR dysfunction or deficiency of 5-alpha-reductase in genetic males causes minimal or absent development of the prostate gland.¹¹⁵ In animals, as well, androgens are critical for the integrity of the prostate gland. Within a week of castration, a rat prostate will undergo involution that results from epithelial cell apoptosis.¹¹⁶ Androgens are also a physiologic prostate cancer promoter. Studies of eunuchoid individuals have suggested that prostates remain small and hypertrophy or prostate cancer does not develop.¹¹⁷ Moreover, animal models of prostate carcinogenesis require the presence of functioning testes or exogenous androgens to support the development of prostatic cancer.^118,119 Transgenic mice engineered for elevated AR expression in the prostate have high turnover of prostatic epithelial cells and develop prostatic intraepithelial neoplasia later in life.¹²⁰ Although it is clear that androgens are essential for the development of prostate cancer, it has been difficult to correlate relative levels of serum androgens with prostate cancer risk. Racial differences in circulating androgen levels have been proposed to account, in part, for differences in prostate cancer incidence and severity. However, the association between prostate cancer incidence and serum androgen levels is controversial and has not been demonstrated conclusively.^121-126 This may be due to the fact that the activity of the ligand receptor may vary and may play an equally important role in prostate cancer promotion.

Genetic variations in the AR that affect its activity have been shown to affect prostate cancer risk. Since excessive NTD CAG repeat length was associated with hypogonadism in Kennedy’s disease, it was suspected that this common polymorphic region could influence AR activity.¹²⁷ In fact, CAG repeat length is inversely related to AR activity in the right cellular milieu.¹²⁸ The dependence of these findings on cell type may be due to the effect that the NTD poly-Q region has on interactions with p160 or other coactivator molecules.¹²⁹ Different studies have shown that shorter CAG repeat length in the AR NTD is associated with the occurrence of more aggressive prostate cancer,¹³⁰ earlier age of onset,^131,132 and likelihood of recurrence.¹³³ Even in low-risk Asian populations that are favored by higher median CAG repeat length, shorter CAG repeat length influences prostate cancer risk.¹³⁴ One smaller study in a European population failed to support the association between CAG repeat length and prostate cancer risk,¹³⁵ and CAG repeat length does not seem to play a role in the inheritance of risk we attribute to familial prostate cancer.¹³⁶ Other alterations of the AR gene, particularly in the 5' untranslated region, have been associated with prostate cancer risk via a still unknown mechanism.¹³⁷

In contrast to the large number of missense AR mutations that have been found in association with androgen insensitivity syndromes, there do not seem to be many AR mutations that predispose to prostate cancer. One example of an inherited AR mutation that confers prostate cancer risk was found in a Finnish kindred. A missense mutation R726L was initially found in a prostate cancer specimen¹³⁸ and then shown to be present in the germline of 0.33% of the Finnish population and 1.91% of Finnish prostate cancer patients (odds ratio, 5.8; P = .006).¹³⁹ This rare mutation probably originated from a single Finnish founder and recently has not been found in the American population.¹⁴⁰

ALTERATIONS OF THE AR GENE IN PROSTATE CANCER
Like the epithelium from which they arise, prostate cancer cells retain responsiveness to and dependence on androgens. It has been know for more than half a century that prostate cancer in most cases retains androgen responsiveness and will undergo regression in response to androgen deprivation.^141,142 Over 80% of men with disseminated prostate cancer will show some clinical response to androgen ablation. However, there is no way to predict which patients will not respond or how long the responding patients will benefit from androgen control of their prostate cancer. Although the median duration of response to hormonal ablation is less than 3 years, response durations range from a few months to many years. Androgen responsiveness in prostate cancer does not correlate with either the presence or the levels of androgen receptor in cancer tissues.^143-148 Furthermore, AR expression persists after the patient no longer enjoys clinical remission induced by androgen deprivation. In general, the AR gene is normal and expressed in primary prostate cancer. However, after hormone deprivation therapy, a number of AR gene alterations have been found. These alterations lead to increased sensitivity of the receptor to low levels of circulating androgens and also to the receptor’s ability to recognize a broadened spectrum of ligands as potent agonists of AR action. All these findings underscore the general notion that the AR signaling pathway is usually maintained in advanced prostate cancer that progresses after first-line androgen ablative therapy.

The use of androgen blockade in the treatment of prostate cancer has expanded in the last 10 years. Because of heightened prostate cancer awareness and intensified screening, more men have been diagnosed with the disease.¹⁴⁹ Androgen deprivation therapy had previously been reserved for patients with metastatic prostate cancer but now is in prolonged use for patients with locally advanced disease as an adjunct to irradiation¹⁵⁰ and also may be applied earlier to patients with minimal metastatic disease.¹⁵¹ As a result, more patients are subjected to the selective pressures leading to the appearance of AR gene amplification and mutations.

Prostate cancer cells respond to hormone deprivation therapy by amplifying AR gene copy number in approximately 25% to 30% of patients who experience disease recurrence. No AR gene amplification was found in pretreatment tissue specimens from the patients in whom AR gene amplification developed.^152-154 The presence of AR gene amplification may reflect an adaptation of the cancer cells to castrate levels of circulating androgens. This is consistent with the finding that patients with AR gene amplification at the time of recurrence on hormone ablation have a higher likelihood of responding to second-line hormonal therapy than those without amplification.^155-157 Interestingly, amplification of the AR gene is also an adaptive response to high-dose antiandrogen monotherapy, reflecting the importance of increased AR signaling for prostate cancer cells.¹⁵⁸ Although there was a suggestion that AR gene amplification was associated with higher levels of circulating prostate-specific antigen,¹⁵⁵ more quantitative analysis of tumor mRNA failed to confirm this association.¹⁵⁹

Hormonal deprivation also seems to lead to the selection of mutations in the AR gene that alter its response to antiandrogens and broaden the spectrum of ligand agonists. The first suggestion that prostate cancer cells could have altered AR came with the observation that the hormone-responsive LNCaP cell line recognized the antiandrogens cyproterone acetate and hydroxyflutamide, the active metabolite of flutamide, as agonists.¹⁶⁰ This phenomenon was explained by the demonstration that LNCaP cell AR contained a T877A mutation that was responsible for the altered pharmacologic activity of the antiandrogens.^161-163 It should be remembered that LNCaP cells were derived from a patient who had been treated with diethylstilbestrol but for whom antiandrogens were not available.¹⁶⁴ Three-dimensional crystallographic analysis has since shown that replacement of the threonine side chain with an alanine alters the size of the steroid-hormone binding pocket to accommodate ligands that the wild-type receptor cannot.⁴² In particular, the pocket in the variant receptor can accommodate larger residues at position 17 of the D ring in the steroid backbone. The function of most AR mutants identified in prostate cancer has not yet been determined. Recently, a yeast-based assay was developed and tested on 44 AR gene mutations found in prostate cancer. The assay depended on AR activity in yeast and therefore was limited by the complement of coactivators and other molecules available to mediate AR action in yeast. However, this assay demonstrated that there was a wind range of functional ramifications of AR mutations in prostate cancer that ranged from loss to gain of function.¹⁶⁵

A number of investigators have detected AR mutations in prostate cancer tissue.^166-174 These mutations are very rare AR mutations in patients with primary prostate cancer and are found with higher frequency in patients with advanced disease, which suggests that mutations in AR occur before hormonal ablative therapy and play a role in prostate tumor progression.¹⁶⁶ Detection of AR mutations depends somewhat on the sensitivity of the experimental approach. Molecular analysis of prostate cancer tissues faces hurdles because of the heterogeneous nature of the tissue samples and of the tumor itself.^175,176 Microdissection of tumor tissue to enrich for cancer cell DNA has yielded a higher fraction of samples with detectable AR mutations.¹⁶⁶ Analysis of primary prostate tissues with epitope-specific AR antibodies and careful microdissection disclosed up to 44% AR mutations in prostate cancer samples.¹⁷⁷ The latter study analyzed primary prostate cancer resected before the widespread use of prostate-specific antigen testing, which suggests that small foci with AR mutations may arise at the later stages of local tumor progression.

The selective pressure of antiandrogen therapy results in yet a higher frequency of detectable AR mutations in tissues from men who have progressive disease after receiving antiandrogens, predominantly flutamide.¹⁷⁸ Mutant receptors have also been found in prostate cancer cell lines and in nude mouse xenografts, further supporting the notion that AR modified to enhance signaling provide a growth advantage for prostate cancer cells.^179,180 The precise incidence rate of AR mutations in prostate cancer is less important than the implications the mutations have for treatment strategy. Selection for AR mutations is probably an important oncogenic step in the development of a subset of prostate cancers. It is apparent that some primary prostate cancers do harbor AR mutations. These mutations arose in the absence of treatment selection and were undoubtedly important for the growth of the primary tumor.

AR mutations in prostate cancer cluster in three regions of the molecule.² In the LBD, mutations cluster in the loop between helices 3 and 4 that is common to many steroid hormone receptors.¹⁸¹ Mutations in the LBD affect the ligand-binding pocket and liberalize the spectrum of AR agonists to a wider range of steroid hormones and pharmaceutical antiandrogens.^161,174,180 AR mutations that affect the ligand-binding pocket do not, except for a single site, overlap at all with binding pocket mutations that cause androgen insensitivity.⁴¹ Since AR mutations in prostate cancer are selected to enhance AR activity and androgen insensitivity mutations decrease activity, this mutual exclusion is not surprising (Fig 2C).

A second cluster is located in the region 874 to 910 that flanks AF-2, the region that affects binding of p160 coactivator molecules and the AR NTD.¹⁸² AR activity is affected in prostate cancer, as well, by alterations in AR coactivators. Hormone-resistant prostate cancer cells often display AR overexpression and overexpression of coactivator molecules important for AR signaling.¹⁸³ Mutations are also found in the hinge region that borders the DBD and the LBD.^41,184 The hinge region seems to be targeted because it affects AR interactions with corepressors and thereby diminishes the efficacy of antiandrogens and may explain the sensitization of AR to ligand interactions in late-stage prostate cancer.¹⁸⁴

Just as steroid hormone receptors initiate transcriptional signals that have to be amplified by coactivators, the signals can be silenced by corepressors.⁹⁴ The hinge region of AR between the DBD and LBD is frequently affected by mutations in prostate cancer. The region ⁶⁶⁸QPIF⁶⁷¹ lies between the hinge and the LBD and forms a hydrophobic cleft that potentially mediates interactions with other proteins, perhaps corepressors. This region is mutated both in prostate cancer and in the transgenic murine prostate cancer TRAMP mouse that develops prostate cancer promoted by organ-specific expression of the simian virus 40 T antigen.^2,184,185 Moreover, deletion of the hinge region amino acids 628 to 646 results in significant activation of the AR and marked enhancement of LXXLL-dependent ligand-dependent coactivation.¹⁸⁶ Interestingly, this region is essentially never affected by mutations associated with androgen insensitivity. This is consistent with the notion that it is primarily a site for corepressor binding and therefore an important target for mutations in prostate cancer (Fig 4). Alternatively, the hinge region may also modulate NTD binding to LBD via the FXXLF motif in the NTD. NTD binding to the LBD can interfere with p160 coactivator binding to the AF-2 groove of the LBD and in this way may modulate the activity of the AR signaling complex.¹¹²

View larger version (37K): [in this window] [in a new window]   Fig 4. Three-dimensional structure of the AR LBD demonstrating the location of mutations common to prostate cancer (A and B) and CAIS (C and D). The ribbon diagrams in B and D are oriented with 90° clockwise rotation from the diagrams in Figure 2. (A) Peptide map of AR LBD showing regions with high frequency of AR gene mutations in prostate cancer. Approximately 79% of AR gene LBD mutations in prostate cancer occur in the three colored regions bound by codons 670 to 678 (red), 701 to 730 (yellow), and 874 to 910 (purple). Two mutations have been found in the hinge (H) region (arrow). (B) Three-dimensional ribbon diagram of the AR LBD bound to testosterone (green) showing alpha helix and beta sheet structures. The ligand is in the ligand-binding pocket, and the LXXLL peptide of the p160 coactivator GRIP1 (yellow/red hatched) is docked in the hydrophobic coactivator-binding cleft formed by helices 3, 4, and 12. Amino acid residues in which missense mutations have been identified in prostate cancer are indicated. The color scheme for regions where mutations are localized is the same as in panel A. (C) Peptide map of AR LBD showing regions with high frequency of AR gene mutations in CAIS. Approximately 79% of AR gene LBD mutations in prostate cancer occur in the three colored regions bound by amino acids 688 to 710 (red), 749 to 780 (yellow), and 831 to 866 (purple). (D) Three-dimensional ribbon diagram as in panel B. Amino acid residues in which missense mutations have been identified in CAIS are located in the colored regions corresponding to the map in panel C. Note that the prostate cancer mutations affect only one side of the ligand-binding pocket. The other regions where prostate cancer mutations cluster affect coactivator or corepressor binding. On the other hand, clusters of mutations in CAIS affect regions that make direct contact with ligand or abolish binding to p160 coactivator proteins. (Figure provided by Wayne Tilley. Figure and parts of the legend are reprinted from Buchanan et al2 by permission of the publisher.)

CONSIDERATIONS FOR THE FUTURE
The last several years have seen a substantial expansion in our understanding of how the AR works and how it differs from other members of the steroid hormone receptor family. It is hoped that these differences will be exploitable in the design of new agents to modulate AR action to achieve clinically important results. We have learned from studying AR mutations from androgen insensitivity syndromes as well as those that occur in prostate cancer. These findings have been complemented with results from a number of laboratories that have characterized in detail the functional interactions of the AR molecule. From these studies, there are four possible targets for pharmacologic intervention: AR binding to ligand, N- and C-terminal interactions, coactivators interaction, and corepressor interactions. As the relationships between each of these interactions and the physiologic manifestations of androgen action are elucidated, the targets for intervention will be clarified and our aim at hitting them will improve. Manipulation of androgen action is used for prostate cancer,¹⁸⁷ benign prostatic hyperplasia,¹⁸⁸ hypogonadism, anemia,¹⁸⁹ control of criminal behavior,¹⁹⁰ and treatment of male pattern baldness.¹⁹¹ Continued expansion of our understand-ing of AR action will contribute to more effective therapies with fewer side effects in all these areas and perhaps more.

	ACKNOWLEDGMENTS

 
Supported by grant nos. CA87855 and CA96854 from the National Institutes of Health, Bethesda, MD.

John Sack, Stanley Krystek, and Wayne Tilley generously provided figures. Wayne Tilley and Mary Ellen Taplin provided valuable discussions about AR mutations. Tapio Visakorpi and Wayne Tilley read the manuscript and graciously provided criticism. Elizabeth Wilson was also kind enough to review the manuscript and provided data before publication.

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Submitted October 3, 2001; accepted April 5, 2002.

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