Review

Correspondence Harvard Medical School, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA

Email mtaplin@partners.org

Introduction

Functional androgen receptor (AR) signaling is necessary for the development of prostate cancer. Inherited syndromes such as androgen insensitivity and spinal and bulbar muscular atrophy have reduced or absent AR signaling, which results in underdeveloped prostates that do not produce carcinomas.^{1, 2} In the 1940s, Huggins and Hodges demonstrated the therapeutic effect of androgen deprivation therapy (ADT) for prostate cancer, and ADT remains the mainstay of systemic therapy despite its transient response duration.³ It has become clear that AR expression and signaling remains intact as the disease evolves from androgen-sensitive cancer to classically (but perhaps inaccurately) termed hormone refractory prostate cancer (HRPC). Genetic and epigenetic changes mean that prostate tumors continue to rely on AR growth signaling, and they thus remain targets of 'hormonal' therapy. The development of new strategies and new drugs that more effectively abrogate AR signaling will probably result in important clinical benefits. This article will review AR structure and function and molecular changes in androgen-independent prostate cancer, and discuss novel AR-targeting compounds.

Androgen receptor structure and function

The AR, the gene for which is located on chromosome Xq11–12, is a member of the steroid hormone receptor family of ligand-activated nuclear transcription factors.⁴ The steroid hormone receptors share a common gene structure with other receptors such as the estrogen, progesterone, glucocorticoid, retinoid, mineralocorticoid and thyroid hormone receptors.⁴ The AR contains four functional regions: an amino terminal regulatory domain (AF-1 site), a DNA-binding domain composed of two zinc fingers, a hinge region containing a nuclear localization signal, and a carboxy-terminal ligand-binding domain (AF-2 site). Unligated ARs are located primarily in the cytoplasm, and are bound to heat shock proteins (HSPs) 90, 70, 56, and 23, which stabilize the ARs' tertiary structure in a conformation that permits androgen binding (Figure 1).^{5, 6}

Figure 1 Androgen receptor structure and function

The binding of DHT results in the assembly of a transcription complex of co-regulatory proteins and transcription of androgen-regulated genes. Abbreviations: AES, amino-terminal enhancer of split; AR, androgen receptor; ARE, androgen response element; C, carboxy terminal; CBP, CREB-binding protein; DBD, DNA-binding domain; DHT, 5-dihydrotestosterone; HAT, histone acetylases; HDAC3, histone deacetylase 3; HDAC6, histone deacetylase 6; HEY1, hairy/enhancer-of-split related with YRPW motif 1; HSP90, heat shock protein 90; LBD, ligand-binding domain; N, amino terminal; NCOR, nuclear corepressor; PCAF, p300/CBP-associated factor; PSA, prostate-specific antigen; RNA pol II, RNA polymerase II; SMRT, silencing mediator of retinoid and thyroid; SRC, nuclear receptor coactivator; TF7L2, transcription factor 7-like 2; TLE, transducin-like enhancer of split.

Full figure and legend (33K)Figures & Tables indexDownload Power Point slide (237K)

Androgen binding to the AR results in dissociation of HSPs from the AR, causing dimerization of the AR and subsequent tyrosine kinase phosphorylation, resulting in translocation of the AR to the nucleus.⁷ Once inside the nucleus, the AR binds to androgen response elements located in the promoter and enhancer regions of target genes, resulting in concomitant recruitment of co-regulatory proteins and formation of an active transcription complex.⁸ Co-regulatory proteins form a bridge between the AR, the preinitiation complex and RNA polymerase; coactivators facilitate transcription by recruiting protein complexes to DNA that alter the chromatin structure to a more transcriptionally active form, and co-repressors mediate chromatin condensation and silence transcription.⁹ Coactivators that have histone acetyltransferase activity include members of the p160 family of proteins such as NCOA1, NCOA2, NCOA3, PCAF, CBP, TIP60 and p300.⁷ Co-repressors include the silencing mediator of retinoid and thyroid (SMRT) hormone receptors, and nuclear receptor co-repressor (NCOR).¹⁰ AR-regulated genes include prostate-specific antigen (PSA), cyclin-dependent kinase 8 (CDK8), the p85 catalytic subunit of phosphatidylinositol 3-kinase (PIK3R1) and RAB4A (a member of the Ras oncogene family of proteins).¹¹ There are also data to indicate that androgens can function nongenomically through AR action in the cytoplasm through the mitogen-activated protein kinase (MAPK) signal cascade; however, the physiologic effects of nongenomic androgen action are still unclear.¹²

Function of the androgen receptor in prostate cancer

Although intact AR signaling is known to be necessary for the development of prostate cancer, the exact role of the AR in prostate cancer initiation is not known. Results from immunohistochemical evaluation demonstrate that AR protein is present in primary, metastatic and HRPC regardless of tumor stage and grade.¹³ AR immunoreactivity is heterogeneous within prostate tumors and, unlike the expression of the estrogen and progesterone receptors in breast cancer, AR expression in prostate cancer has no apparent correlation with prognosis or with duration of response to ADT.¹⁴ A small proportion (approximately 8%) of patients with HRPC lose AR expression, presumably through AR promoter methylation; whether these tumors carry a poor prognosis is not known.¹⁵

The AR is composed of eight exons. Exon A serves mainly for transactivation, exons B and C for DNA binding, and exons D–H for hormone binding. Exon A comprises nearly 50% of the coding region and contains two regions of repetitive DNA triplet repeat sequences: CAG and GCC. The genomic number of these repeats has been implicated in the development of prostate cancer and aggressiveness of established tumors.^{16, 17, 18} The CAG repeat length is usually between 14 and 35 repeats in individuals without prostate cancer and the median number of repeats has divergent ethnic median distributions, with African Americans having on average the shortest repeat lengths (19 repeats) and Asians the longest (21 repeats).¹ In vitro studies of short CAG repeat lengths correlated with a more transcriptionally active receptor, perhaps because of increased protein stability.^{19, 20} There have been conflicting reports correlating CAG repeat length with prostate cancer incidence among ethnic groups. One report demonstrated that prostate cancer incidence among different ethnic groups (i.e. African Americans, whites and Asian Americans) correlated with the average length of the CAG repeat.¹⁷ African Americans (who generally have the shortest CAG repeats) had the highest prostate cancer incidence and Asians with the longest CAG repeat lengths had the lowest incidence; however, this correlation or functional significance has not been validated in large, prospective analyses.

Androgen receptor alterations and prostate cancer progression

Systemic prostate cancer is treated with ADT and, over a time period of approximately 12–48 months, HRPC can become established. Patients with metastatic disease will generally develop HRPC sooner than patients with early-stage disease (i.e. those with rising PSA only);^{21, 22} however, the determinants of response duration to ADT have not been elucidated.

AR gene amplification has been reported in 25–30% of patients with HRPC but is present at very low rates (1–2%) in those with primary prostate cancer, indicating that AR amplification is involved in the development of HRPC.^{23, 24, 25, 26, 27, 28} AR gene amplification was associated with an increased mRNA expression and augmented levels of AR protein.²⁴ It has also been shown that patients with HRPC may have increased AR expression in the absence of AR amplification, which might occur via increased transcription rates, or stabilization of the AR mRNA or protein.^{7, 24} Compared with patients without AR amplification, patients harboring AR-amplified tumors had longer response duration to ADT and a longer median survival after development of HRPC.^{18, 26} In addition, patients with AR amplification had an increased likelihood of responding to second-line hormone therapies compared with patients without amplified tumors.^{26, 29} Amplifications of the AR gene highlight the strong selective pressure for continued AR signaling as tumors evolve in an environment of androgen deprivation, and provides impetus for development of more-effective AR signal inhibition.

Point mutation of the AR can result in altered ligand specificity such that mutated ARs can be activated by non-androgenic ligands such as antiandrogens. The first mutated AR was cloned from the LNCaP human prostate adenocarcinoma cell line. The mutation, at codon 877 of the ligand-binding domain of the AR, is activated by progesterone, estradiol, cyproterone acetate, and the antiandrogens nilutamide and hydroxyflutamide.³⁰ All AR mutations that have been associated with human diseases, including prostate cancer, have been recorded in a database.³¹ The true incidence of AR mutations in prostate cancer is not known, but it is probably in the range of 10–40% depending on antecedent exposure to compounds, which can apply selective pressure for AR mutation.^{18, 32} For example, AR mutation was found in 5 of 16 patients previously treated with long-term hydroxyflutamide, compared with only 1 of 17 patients who did not receive this drug.³³ In transfection-based assays, these mutant receptors were activated by hydroxyflutamide but not by other antiandrogens such as bicalutamide.³⁴ Patients treated with ADT including hydroxyflutamide were more likely to response to second-line bicalutamide therapy than those who did not receive ADT.³⁵

In a prospective analysis of patients undergoing antiandrogen withdrawal, 48 bone marrow biopsies containing prostate tumor were analyzed for AR mutation; mutations in regions coding for the ligand-binding domain of AR were found in 10% of patients, and were equally distributed in those who received prior hydroxyflutamide or bicalutamide therapy.³⁶ The low frequency of AR mutations might have resulted from a shorter duration of antiandrogen exposure that had become the norm over the course of the trial. No correlation between antiandrogen withdrawal response and AR mutations could be made because of the small number of patients with AR mutations. There was no difference in the overall survival of subjects with and without AR mutations.

The physiologic significance of AR mutation seems in some cases to be related to broadened ligand specificity. The majority of mutations cluster in three areas of the AR, which comprise about 8% of the coding sequence.^{7, 32} AR mutations in codons 701–730 result in AR activation by adrenal androgens, glucocorticoids, and progesterone.^{37, 38, 39} Mutations in the area flanking the AF-2 region (i.e. codons 874–910) also broaden ligand specificity, including activation by the agents hydroxyflutamide and cyproterone acetate.^{30, 33} Mutations also occur in codons 670–678 of the AR, which code for the region between the hinge and ligand-binding domains, and functionally these mutant AR proteins have increased response to 5-dihydrotestosterone (DHT).⁴⁰ When an agonist, such as hydroxyflutamide, binds to a mutated AR, the conformation of the ligand–receptor complex changes relative to wild-type AR such that a coactivator binding site is generated. Thus, AR mutations occurring in patients with prostate cancer have a growth advantage not only by loosening the ligand-binding pocket and expanding the range of agonists, but also by changing the interaction between co-regulatory molecules that favor cell growth. There has been one report of a mutation at Gln640Ser producing a truncated AR resulting in constitutive activation in the absence of ligand.^{7, 41}

Alterations in the balance between AR coactivator and co-repressor expression may result in a growth advantage for prostate cancer cells, and thus co-regulatory proteins are potential drug targets. Gregory et al. demonstrated that levels of the coactivators NCOA1 and NCOA2 increased with elevations in AR expression in HRPC.⁴² In vitro overexpression of NCOA2 with wild-type or mutant AR demonstrated that physiologic concentrations of androstenedione, estradiol and progesterone were potent AR agonists. In an independent analysis, Halkidou et al. studied the 60 kDa coactivator Tat interactive protein (TIP60) and found that 87% of HRPC specimens demonstrated nuclear accumulation of TIP60, compared with a more diffuse cellular distribution in noncancerous or androgen-dependent cancer.⁴³ AR transactivation is, therefore, controlled by the interplay between ligands and co-regulatory proteins, and co-regulatory proteins are probably regulated by post-translational modifications such as phosphorylation, acetylation, and methylation.⁴⁴

Ligand-independent AR activation might have a role in the development of HRPC. Peptide growth factors such as ERBB2, insulin-like growth factor, keratinocyte growth factor and epidermal growth factor can also activate AR. These growth factors are ligands for receptor tyrosine kinases, and activation of one or several of the tyrosine kinase pathways could promote AR activation and growth in low-androgen environments. The cytokine interleukin 6 can signal via p300, ERBB2, signal transducers and activators of transcription (STAT) or MAPK and increase the expression of AR-regulated genes in the absence of androgens.⁴⁵ Other proteins that can interact with AR include -catenin, caveolin-1, cyclin E, cyclin D₁, Rb, p53, c-Jun, SMAD3 and guanine nucleotide-binding G_s proteins (G proteins).⁴⁶ G-protein-coupled receptors mediate cellular responses to a wide variety of extracellular molecules including lipid and peptide growth factors.⁴⁷ Kasbohm et al. have demonstrated that the alpha subunit of the G_s protein can activate AR in prostate cancer cells in the absence of androgen stimulation and synergizes with low concentrations of androgen to more fully activate the AR.⁴⁸ Further investigation will determine the physiologic significance of these interactions.

The androgen receptor as a therapeutic target

Standard hormone therapy for prostate cancer includes a variety of approaches to directly reduce the ligand (androgen) or interfere with the ability of the ligand to interact with the AR. Contemporary treatment options, however, reduce but do not eliminate androgen at the target tissue, namely prostate cancer cells. Orchiectomy, and luteinizing hormone-releasing hormone (LHRH) agonists and antagonists suppress circulating androgen by 90–95%.⁴⁹ Intraprostatic (as well as metastatic prostate cancer) concentrations of DHT are only reduced by 50–70% following medical or surgical castration.⁵⁰ The adrenal glands secrete the precursor steroid dehydroepiandrosterone, which is converted to testosterone and DHT in peripheral tissues. After castration, plasma concentrations of the androgen metabolites androsterone glucuronide and 3-diol-G (5-androstane-3-17-diol-glucuronide) remained at 28% and 37% respectively of control levels, which reflects conversion of adrenal androgens to DHT in prostate tissue.⁵⁰ Mohler et al. have measured intraprostatic concentrations of testosterone in HRPC samples and found the levels to be similar to those of untreated benign disease.⁵¹ The levels of DHT (1.45 nmol/l) were sufficient to maintain AR signaling and expression of PSA.^{51, 52} One study that assessed 33 HRPC samples using Affymetrix oligonucleotide microarrrays demonstrated increased expression of the AR and of genes mediating androgen metabolism, including the enzyme AKR1C3, which reduces conversion of adrenal androstenedione to testosterone.⁵³

Second-line hormone therapies in prostate cancer are directed at either blocking AR-ligand interaction with antiandrogens or antiandrogen withdrawal or reducing ligand by inhibiting adrenal androgen synthesis.⁵⁴ Approved antiandrogens include bicalutamide, hydroxyflutamide and nilutamide, and adrenal androgen synthesis is commonly inhibited with corticosteroids, ketoconazole or aminoglutethimide. Ketoconazole is thought to inhibit adrenal androgen synthesis by nonselectively inhibiting several cytochrome P450 enzymes involved in adrenal steroid synthesis. Clinical and PSA responses to these therapies range between 20% and 40%, with a median duration of response of about 5 months.^{35, 55} A minority of patients will have durable responses of 2–4 years. The limited utility of available second-line hormone therapies is probably the result of incomplete AR inhibition. Incomplete abrogation of adrenal androgen synthesis is compounded by the ability of prostate tumor to create hypersensitive receptors and produce androgen through intracrine mechanisms. Our understanding of the endocrinology and molecular biology of HRPC supports the hypothesis that AR signaling remains a key growth pathway. Effective, novel agents that target AR signaling are discussed below.

Novel targeted androgen receptor approaches

Many novel therapeutic approaches to targeting AR signaling are being investigated in vitro and in animal models. Fewer compounds are in phase I/II clinical trials and there are no new AR-targeted therapeutics in phase III testing. Although adrenalectomy has demonstrated efficacy in prostate cancer, and in combination with castration would result in maximum adrenal androgen suppression, the procedure is invasive, systemically toxic because of adrenal insufficiency and is unlikely to be re-evaluated in prostate cancer patients at this time.⁵⁶ More-effective compounds to induce a medical adrenalectomy are, therefore, being developed (Table 1).

Table 1 Novel compounds directed at androgen receptor signaling in testing for prostate cancer

Full tableFigures & Tables indexDownload Power Point slide (238K)

Conclusion

This Review focused on the role of the AR in HRPC and novel AR-targeted therapeutics. Many exciting new cancer therapeutics are in development including gene therapy, growth factor inhibitors, signal transduction inhibitors, apoptosis regulators, cell-cycle regulators, proteasome inhibitors, antiangiogenesis agents, antimetastatic agents, retinoids, epigenetic therapeutics, cytotoxics and telomerase inactivators.⁸⁴ It is probable that the most effective prostate cancer therapy will result from a multitargeted approach, perhaps combining maximal AR inhibition with inhibition of a parallel AR-related growth pathway.

References

1. Caskey C et al. (1992) Triplet repeat mutations in human disease. Science 256: 784–789 | Article | PubMed | ISI | ChemPort |
2. Griffin J (1992) Androgen resistance—the clinical and molecular spectrum. N Engl J Med 326: 611–618 | PubMed | ChemPort |
3. Huggins C and Hodges C (1941) The effect of castration, of oestrogen and of androgen injections on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1: 293–297 | ISI | ChemPort |
4. Evans R (1988) The steroid and thyroid hormone receptor super family. Science 240: 889–895 | Article | PubMed | ISI | ChemPort |
5. Pratt W and Toft D (1997) Steroid receptor interactions with heat shock protein and immunophilin charperones. Endocr Rev 18: 306–360 | Article | PubMed | ISI | ChemPort |
6. Veldscholte J et al. (1992) Hormone-induced dissociation of the androgen receptor-heat shock protein complex: use of a new monoclonal antibody to distinguish transformed from nontransformed receptors. Biochemistry 31: 7422–7430 | Article | PubMed | ChemPort |
7. Dehm SM and Tindall DJ (2005) Regulation of androgen receptor signaling in prostate cancer. Expert Rev Anticancer Ther 5: 63–74 | Article | PubMed | ISI | ChemPort |
8. Shang Y et al. (2002) Formation of the androgen receptor transcription complex. Mol Cell 9: 601–610 | Article | PubMed | ISI | ChemPort |
9. Chang CY and McDonnell DP (2005) Androgen receptor-cofactor interactions as targets for new drug discovery. Trends Pharmacol Sci 26: 225–228 | Article | PubMed | ChemPort |
10. Mckenna J et al. (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20: 321–344 | Article | PubMed | ISI | ChemPort |
11. Velasco A et al. (2004) Identification and validation of novel androgen-regulated genes in prostate cancer. Endocrinology 145: 3913–3924 | Article | PubMed | ISI | ChemPort |
12. Heinein C and Chang C (2002) The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol 16: 2181–2187 | Article | PubMed | ISI | ChemPort |
13. Ruizeveld de Winter JA et al. (1991) Androgen receptor expression in human tissues: an immunohistochemical study. J Histochem Cytochem 39: 927–936 | PubMed | ChemPort |
14. de Vere White R et al. (1997) Human androgen receptor expression in prostate cancer following androgen ablation. Eur Urol 31: 1–6 | PubMed | ChemPort |
15. Sasaki M et al. (2002) Methylation and inactivation of estrogen, progesterone, and androgen receptors in prostate cancer. J Natl Cancer Inst 94: 384–390 | PubMed | ChemPort |
16. Giovannucci E et al. (1997) The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 94: 3320–3323 | Article | PubMed | ChemPort |
17. Irvine R et al. (1995) The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 55: 1937–1940 | PubMed | ISI | ChemPort |
18. Taplin ME and Balk SP (2004) Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence. J Cell Biochem 91: 483–490 | Article | PubMed | ISI | ChemPort |
19. Chamberlain N et al. (1994) The length and location of the CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22: 3181–3186 | Article | PubMed | ISI | ChemPort |
20. Choong C et al. (1996) Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 10: 1527–1535 | Article | PubMed | ISI | ChemPort |
21. Eisenberger M et al. (1998) Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339: 1036–1042 | Article | PubMed | ISI | ChemPort |
22. Moul JW et al. (2004) Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 171: 1141–1147 | Article | PubMed |
23. Bubendorf L et al. (1999) Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res 59: 803–806 | PubMed | ISI | ChemPort |
24. Edwards J et al. (2003) Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 89: 552–556 | Article | PubMed | ISI | ChemPort |
25. Ford OH et al. (2003) Androgen receptor gene amplification and protein expression in recurrent prostate cancer. J Urol 170: 1817–1821 | Article | PubMed | ISI | ChemPort |
26. Koivisto P et al. (1997) Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 57: 314–319 | PubMed | ISI | ChemPort |
27. Linja M et al. (2001) Amplification and over expression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 61: 3550–3555 | PubMed | ISI | ChemPort |
28. Visakorpi T et al. (1995) In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 9: 401–406 | Article | PubMed | ISI | ChemPort |
29. Palmberg C et al. (2000) Androgen receptor gene amplificaiton at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer. J Urol 164: 1992–1995 | Article | PubMed | ISI | ChemPort |
30. Veldscholte J et al. (1990) A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 173: 534–540 | Article | PubMed | ISI | ChemPort |
31. Gottlieb B et al. (2004) The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 23: 527–533 | Article | PubMed | ChemPort |
32. Gelmann E (2002) Molecular biology of the androgen receptor. J Clin Oncol 20: 3001–3015 | Article | PubMed | ISI | ChemPort |
33. Taplin ME et al. (1999) Selection for androgen receptor mutations in prostate cancer treated with androgen antagonist. Cancer Res 59: 2511–2515 | PubMed | ISI | ChemPort |
34. Fenton M et al. (1997) Functional characterization of mutant androgen receptors from androgen independent prostate cancer. Clin Cancer Res 3: 1383–1388 | PubMed | ChemPort |
35. Joyce R et al. (1998) High dose bicalutamide for androgen independent prostate cancer: Effect of prior hormonal therapy. J Urol 159: 149–153 | Article | PubMed | ChemPort |
36. Taplin ME et al. (2003) Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia group B study 9663. J Clin Oncol 21: 2673–2678 | Article | PubMed | ISI | ChemPort |
37. Culig Z et al. (1993) Mutant androgen receptor detected in an advanced-stage prostate carcinoma is activated by adrenal androgen and progesterone. Mol Endocrinol 7: 1541–1550 | Article | PubMed | ISI | ChemPort |
38. Culig Z et al. (1996) Activation of two mutant androgen receptors from human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone. Cancer Detect Prev 20: 68–75 | PubMed | ChemPort |
39. Zhao X et al. (2000) Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med 6: 703–706 | Article | PubMed | ISI | ChemPort |
40. Buchanan G et al. (2001) Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function. Mol Endocrinol 15: 46–56 | Article | PubMed | ISI | ChemPort |
41. Ceraline J et al. (2004) Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer. Int J Cancer 108: 152–157 | Article | PubMed | ChemPort |
42. Gregory C et al. (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61: 4315–4319 | PubMed | ISI | ChemPort |
43. Halkidou K et al. (2003) Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene 22: 2466–2477 | Article | PubMed | ISI | ChemPort |
44. Papaioannou M et al. (2005) Co-activator and co-repressor interplay on the human androgen receptor. Andrologia 37: 211–213 | Article | PubMed | ChemPort |
45. Ueda T et al. (2002) Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways. J Biol Chem 277: 7076–7085 | Article | PubMed | ISI | ChemPort |
46. Grossmann M et al. (2001) Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst 93: 1687–1697 | Article | PubMed | ChemPort |
47. Ford C et al. (1998) Molecular basis for interactions of G proteins betagamma subunits with effectors. Science 280: 1271–1274 | Article | PubMed | ISI | ChemPort |
48. Kasbohm E et al. (2005) Androgen receptor activation by Gs signaling in prostate cancer cells. J Biol Chem 280: 11583–11589 | Article | PubMed | ISI | ChemPort |
49. Waxman J et al. (1983) Treatment with gonadotropin-releasing hormone analogue in advanced prostatic cancer. BMJ 286: 1309–1312 | PubMed | ChemPort |
50. Labrie F et al. (2005) Is dehydroepiandrosterone a hormone? J Endocrinol 187: 169–196 | Article | PubMed | ISI | ChemPort |
51. Mohler J et al. (2004) The androgen axis in recurrent prostate cancer. Clin Cancer Res 10: 440–448 | Article | PubMed | ISI | ChemPort |
52. Scher H and Sawyers C (2005) Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 23: 8253–8261 | Article | PubMed | ISI | ChemPort |
53. Stanbrough M et al. (2006) Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res 66: 2815–2825 | Article | PubMed | ISI | ChemPort |
54. Small EJ and Vogelzang NJ (1997) Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 15: 382–388 | PubMed | ChemPort |
55. Small EJ et al. (2004) Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 22: 1025–1033 | Article | PubMed | ChemPort |
56. Bhanalaph T et al. (1974) Current status of bilateral adrenalectomy on advanced prostate carcinoma. Ann Surg 179: 17–23 | PubMed | ChemPort |
57. Attard G et al. (2005) Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int 96: 1241–1246 | Article |