Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone.
Journal: 2012/January - Clinical Cancer Research
ISSN: 1078-0432
Abstract:
High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate).
Relations:
Content
Citations
(24)
References
(60)
Diseases
(1)
Drugs
(2)
Chemicals
(2)
Organisms
(1)
Processes
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Clin Cancer Res 17(18): 5844-5849

Potential prostate cancer drug target: Bioactivation of androstanediol by conversion to dihydrotestosterone

BACKGROUND

Normal male sex development and growth depend on high affinity binding of dihydrotestosterone (DHT, 5α-androstan-17β-ol-3-one), the 5α-reduced product of testosterone (T, 4-androsten-17β-ol-3-one), to the androgen receptor (AR), an essential ligand-dependent transcription factor that regulates androgen-dependent gene transcription. AR binds T and DHT with similar high equilibrium binding affinity (equilibrium dissociation constant, Kd ~0.3 nM) (1), and T and DHT are the only naturally occurring steroids that activate wild-type AR. AR is not activated directly by binding either 5α-androstane-3α,17β-diol (androstanediol) or dehydroepiandrosterone (DHEA). Androgen specificity for AR transcriptional signaling is achieved through the highly structured AR ligand binding domain, and the selective ability of T and DHT to induce the AR NH2- and carboxyl-terminal interaction that stabilizes AR and increases transcriptional activity (2, 3). The well established differences in potency between T and DHT (4) result not from differences in AR equilibrium androgen binding affinity, but from the greater hydrophobicity of DHT that strengthens human AR intermolecular interactions, slows the dissociation rate of bound androgen, and stabilizes the ligand-bound AR to render DHT a more active androgen than T (1, 5).

The requirement for DHT in normal prostate growth and development of the external genitalia is demonstrated by the 5α-reductase syndrome. An inactivating mutation in the type 2 isoform of the 5α-reductase enzyme that converts T to DHT results in a small prostate gland and predominantly female or ambiguous external phenotype in affected newborn males with 46XY chromosomes (6). The 5α-reductase syndrome provides physiological evidence that circulating DHT arises from T, and that DHT is required for normal male sex development. On the other hand, untreated 5α-reductase syndrome patients begin to virilize at puberty. This suggests that the pubertal rise in T compensates for low DHT, or that a pubertal rise in the type 1 isoform of 5α-reductase (7, 8) acts on other steroid precursors such as 17α-hydroxyprogesterone to form 5α-pregnane-17α-ol-3,20-dione and eventually DHT (Fig. 1).

An external file that holds a picture, illustration, etc.
Object name is nihms301495f1.jpg
Backdoor pathway of DHT synthesis involves the conversion of androstanediol to DHT by 17β-HSD6

Conversion of cholesterol to prenenolone by the P450 side chain cleavage enzyme (P450ssc) is the first committed step in steroid biosynthesis. The 17α-hydroxylase/17,20-lyase (P450c17) catalyzes multiple 17α-hydroxylase and 17,20-lyase reactions in the steroidogenic pathway that require P450 oxidoreductase (P450ox/red) electron transfer. P450c17 coded by the CYP17A1 gene is the target for inhibition by abiraterone acetate. Progesterone, 17α-hydroxyprogesterone (17α-OH-progesterone) and testosterone are substrates for 5α-reductase type 1, 2 or 3 (5αR1, 2 or 3). Finasteride is an 5αR2 inhibitor. Dutasteride is an inhibitor of 5αR1, 5αR2 and 5αR3. Isozymes of 3β-hydroxysteroid dehydrogenase (3βHSD), 17β-hydroxysteroid dehydrogenase (17βHSD) and aldo-keto reductase (AKR1C3) are often reversible enzymes with oxidative and reductive activities that require nicotinamide adenine dinucleotide cofactors. Testosterone and DHT are the two biologically active androgens that activate AR. Testosterone is the major circulating active androgen formed in the testis. DHT is formed from testosterone in the testis, and can be synthesized in a so-called backdoor pathway (green) from progesterone and androsterone precursors independent of DHEA, androstenedione or testosterone intermediates.

AR is a critical transcriptional regulator required to establish the normal male sex phenotype, and for the development and progression of prostate cancer (911). Regression of prostate cancer after medical or surgical androgen deprivation therapy is followed invariably by the development of castration-recurrent or castration-resistant prostate cancer (CRPC), which demonstrates an initial reliance of prostate cancer growth on AR mediated gene transcription in response to DHT. AR levels are often increased in CRPC consistent with the continued expression of AR-stimulated genes (12). Additional growth stimulating mechanisms in CRPC include increased levels of AR coregulators, transcription factors and/or phosphorylation that render AR more sensitive to much lower levels of intratumoral androgen, and growth factor and cytokine activation independent of androgen. AR mutations, though rare in prostate cancer, can decrease specificity of AR steroid binding that results in a more promiscuous transcriptional activator that responds to a broader range of ligands (1316).

Recent studies highlight the potential importance of intratumoral androgen biosynthesis in prostate cancer (1722). Mass spectrometry measurements of CRPC tissue extracts indicated ~2 nM DHT sufficient to activate AR (17, 18). In agreement with these findings, finasteride, a 5α-reductase type 2 inhibitor, or dutasteride, a dual 5α-reductase types 1 and 2 inhibitor (Fig. 1), were ineffective in preventing prostate cancer development (23, 24) or in treating aggressive prostate cancer (25, 26). One interpretation of these clinical studies is that alternative androgen biosynthetic pathways provide sufficient DHT to activate AR in the abnormal cellular environment of prostate cancer. CRPC also is characterized by increased expression of a family of related p160 coactivators, named for their approximate 160 kDa molecular weight, and other coregulators that enhance AR sensitivity to low level androgens (27, 28). One example is the AR coregulator, melanoma antigen-A11 (MAGE-11), whose mRNA levels increase in ~30% of CRPC. In one patient with rapidly progressing prostate cancer, MAGE-11 mRNA levels were three orders of magnitude above the normal range, whereas AR mRNA in this patient sample was undetectable using quantitative reverse transcription-polymerase chain reaction (RT-PCR) (28). These findings suggest that highly plastic prostate cancer cells utilize alternative mechanisms to eventually escape drug treatments that target AR.

METABOLISM OF ANDROSTANEDIOL TO DHT

The classical pathway for DHT synthesis is conversion in the testis of the major adrenal androgen androstenedione to T, followed by irreversible 5α-reduction of T to DHT by 5α-reductase type 2 in prostate and other, but not all, androgen target tissues (Fig. 1) (29). Studies in the beagle dog (30) and tammar wallaby (31, 32) indicate an alternative backdoor pathway of DHT synthesis that utilizes androstanediol as precursor instead of T. Androstanediol is the major degradation product of DHT from the reductive 3α-hydroxysteroid dehydrogenase (HSD) activity of 3α-HSD aldo-keto reductases 1C (AKR1C) (Fig. 1), enzymes with both 3- and 17-ketosteroid reductase activity (3338). AR binds androstanediol with moderate affinity, but androstanediol must be converted to DHT to induce transactivation by wild-type AR. Enzymes that convert androstanediol to DHT include 17β-hydroxysteroid dehydrogenase 6 (17β-HSD6 or HSD17B6, known also as retinol dehydrogenase (RODH) 3α-HSD) (39), 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10 or HSD17B10) (40), retinol dehydrogenase 5 (RDH5) (39), dehydrogenase/reductase short-chain dehydrogenase/reductase family member 9 (DHRS9) (33, 41) and retinol dehydrogenase 4 (RODH4) (42).

Recent studies suggest that benign human prostate and prostate cancer cells express predominantly 17β-HSD6 as the major enzyme that converts androstanediol to DHT, and it is DHT that accounts for AR transactivation in the presence of androstanediol (43). Precise measurements of relative enzyme activity of several hydroxysteroid dehydrogenases active in this reaction are complicated by the requirement for optimal pH and nicotinamide adenine dinucleotide cofactors. However, 17β-HSD6 mRNA levels determined using RT-PCR and protein levels on immunoblots suggest a direct link between 17β-HSD6 expression, bioconversion of androstanediol to DHT, and AR activation in the presence of androstanediol.

Androstanediol is not a major adrenal androgen. Thus, to serve as a significant intracellular precursor for DHT synthesis, androstanediol must be synthesized from steroid precursors earlier in the biosynthetic pathway. The backdoor pathway of DHT biosynthesis in benign prostate and prostate cancer cells depends on intracellular 5α-reductase type 1 and 2 isoforms, and the conversion of androsterone to androstanediol or androstanedione (Fig. 1). In both pathways, 17α-hydroxyprogesterone serves as a principal intermediate independent of DHEA, androstenedione or T. Progesterone and 17α-hydroxyprogesterone were shown to be excellent substrates for 5α-reductase type 1 and 2 (8, 44) that form dihydroprogesterone and 17α-hydroxydihydroprogesterone, respectively (Fig. 1). 5α-reductase type 1 predominates in this reaction, and expression of 5α-reductase type 1 increases during prostate cancer progression (45, 46) and possibly in prostate cancer tissue during androgen deprivation therapy (47). A recently described ubiquitously expressed 5α-reductase type 3 isoform is present at higher levels in prostate cancer (48, 49). Although 17α-hydroxyprogesterone is not considered an important sex steroid precursor in normal human physiology (8), increased levels of 5α-reductase types 1 and 3 may facilitate conversion in this pathway that culminates in the formation of DHT.

Continuing in this pathway, reductive 3αHSD converts 17α-hydroxydihydroprogesterone to 17α-hydroxyallopregnanolone (Fig. 1). 17α-hydroxylase/17,20 lyase (P450c17) acts on 17α-hydroxyallopregnanolone to form androsterone. Once androsterone is formed, two possible pathways involve 17β-HSD6 to catalyze the formation of DHT. 17β-HSD6 converts androsterone to androstanedione, which is converted to DHT by 17βHSD3. Androsterone is converted to androstanediol by 17βHSD3 (50), and androstanediol is converted to DHT by 17β-HSD6. The complementary DNA for 17β-HSD6 was originally cloned from prostate (39). 17β-HSD6 is central to the backdoor pathway of DHT synthesis independent of circulating T, appears to be a critical enzyme in prostate cancer cells, and is a potential drug target for treating prostate cancer.

CLINICAL-TRANSLATIONAL ADVANCES

Accumulating evidence that intratumoral androgen production drives prostate cancer growth by activating AR has driven efforts to identify new drugs that target enzymes responsible for androgen biosynthesis. Clinical trials using the 5α-reductase inhibitors finasteride and dutasteride have achieved success in the treatment of benign prostate enlargement but less so for prostate cancer. Critical evaluation of new opportunities to interrupt androgen metabolism has been difficult for several reasons. Steroid metabolic enzymes often exist as multiple isozymes, enzyme function cannot be predicted based on enzyme protein or mRNA levels alone, and in vitro assay conditions may differ from the microenvironment of prostate cancer cells. Enzymes, substrates and products may be at low levels and enzymatic action may differ among tissue compartments so that whole tissue assays are misleading. In addition, fundamental knowledge gaps exist in androgen transport across membranes, such as how androgens transit the vascular endothelium.

The human CYP17A1 gene codes for P450c17, an enzyme with dual functions in the intracrine metabolism of testosterone and DHT from progesterone via the cholesterol pathway (Fig. 1). 17α-hydroxylase and 17,20-lyase activities of P450c17 act on pregnenolone and progesterone precursors to produce DHT via 5α-pregnane-3α,17α-diol-20-one through the backdoor pathway. Ketoconazole is a nonspecific weak inhibitor of P450c17 with limited antitumor properties and excessive toxicity. Recent appreciation of intracrine metabolism of active androgens from adrenal precursors, and the efficacy but high toxicity of ketoconazole led Attard, deBono and colleagues to search for a “better ketoconazole.”

Abiraterone acetate is an irreversible inhibitor of the 17α-hydroxylase and lyase activities of P450c17 (51). Abiraterone acetate suppresses 17α-hydroxylation of pregnenolone and progesterone, and the 17,20-lyase activity of P450c17 that converts 17α-hydroxypregnenolone to DHEA, and 17α-hydroxyprogesterone to androstenedione (Fig. 1) (8). Because 17α-hydroxyprogesterone is a precursor of androsterone and androstanediol, abiraterone acetate would be expected to inhibit the backdoor pathway of DHT synthesis. Although serum androgen, estrogen and PSA levels were suppressed by abiraterone acetate, overall effects were often transient, and prolonged use was associated with a compensatory increase in ACTH and mineralocorticoid excess (52). The duration of response to abiraterone acetate monotherapy and abiraterone-corticosteroid combination therapy ranges from 9 to 14 months, with the response associated with high levels of adrenal androgens prior to initiation of therapy (53). These findings were consistent with a report that higher circulating adrenal androgen was associated with longer survival in men with CRPC (54).

Failure to achieve long term benefit from 5α-reductase or P450c17 inhibitors in the treatment of prostate cancer may result from incomplete enzyme inhibition, a compensatory rise in intratumoral T, alternative pathways of DHT synthesis, or increased AR sensitivity to low androgen in association with increased levels of AR coregulators and AR phosphorylation (55, 56). When androstanediol was provided as substrate, 17β-HSD6 was the major enzyme that converted androstanediol to DHT in normal human prostate and prostate cancer cells. Enzymatic conversion of androstanediol to DHT represents a new potential drug target to block prostate cancer progression that raises several questions. First, the extent to which 17β-HSD6 is responsible for androstanediol conversion to DHT in prostate cells remains unclear. Other enzymes such as DHRS9 and RDH5 may be active. In support of 17β-HSD6 as a drug target, AR transactivation in the presence of androstanediol correlated directly with 17β-HSD6 mRNA and protein in different cell types. However, 17β-HSD6 mRNA levels declined with time after castration in the androgen-dependent CWR22 human prostate cancer xenograft model and in human specimens, whereas DHRS9 and RDH5 mRNA levels were relatively unchanged after castration. 17β-HSD6 could maintain DHT levels sufficient to activate AR, or rely on the activity of other enzymes. A key to defining 17β-HSD6 as a drug target in the treatment of prostate cancer will be to establish the relative contribution of other enzymes that maintain AR activation by androgen precursors.

A second consideration is the redundancy of androgen biosynthetic pathways that suggests prostate cancer cells deprived of testicular androgens recruit multiple mechanisms for the intracrine synthesis of DHT, the most potent naturally occurring AR ligand. A greater clinical response may be achieved through the use of inhibitors directed at different points along the pathway, with a longer lasting clinical response in advanced prostate cancer when a putative 17β-HSD6 inhibitor is combined with the dual 5α-reductase inhibitor dutasteride, LHRH agonist or AR antagonist. Such a multi-pronged approach could provide greater clinical benefit when administered earlier in the course of disease progression prior to the onset of CRPC.

Recent evidence has suggested the existence of constitutively active AR splice variants that lack the ligand binding domain and contribute to prostate cancer progression independent of intratumoral androgen (5760). However, AR is highly susceptible to degradation in the low androgen environment of prostate cancer cells, such that partial AR degradation could account for some reported smaller forms (61). Although higher levels of AR splice variants were reported in certain prostate cancer cell lines (58) that are often subject to complex chromosome abnormalities, AR variants were in much lower abundance in prostate cancer specimens relative to full-length AR (57, 60). Overall the findings support the potential clinical usefulness of drugs that target androgen biosynthesis to achieve temporary reduction in tumor growth.

Acknowledgments

We are grateful for the assistance of Andrew T. Hnat in preparing the figure.

Grant Support

National Cancer Institute (NCI) P01-CA77739, NCI Cancer Center Support Grant to Roswell Park Cancer Institute CA16156 and the University of North Carolina at Chapel Hill Lineberger Cancer Center CA34026, US Public Health Service Grants HD16910 from the National Institute of Child Health and Human Development, and Department of Defense Prostate Cancer Research Program PC094304.

Department of Urology, Roswell Park Cancer Institute, Buffalo, NY
Department of Urology, University at Buffalo, State University of New York, Buffalo, NY
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
Laboratories for Reproductive Biology, Department of Pediatrics and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC

Abstract

High affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiological conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α,17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT that binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to LHRH agonists or antagonists, AR antagonists, inhibitors of 5α-reductase enzymes, finasteride or dutasteride, and steroid metabolism enzyme inhibitors, ketoconazole or the recently available abiraterone acetate.

Abstract

Footnotes

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest are disclosed.

Footnotes

REFERENCES

REFERENCES

References

  • 1. Wilson EM, French FSBinding properties of androgen receptors: evidence for identical receptors in rat testis, epididymis, and prostate. J Biol Chem. 1976;251:5620–5629.[PubMed][Google Scholar]
  • 2. Kemppainen JA, Langley E, Wong CI, Bobseine K, Kelce WR, Wilson EMDistinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone. Mol Endocrinol. 1999;13:440–454.[PubMed][Google Scholar]
  • 3. He B, Kemppainen JA, Wilson EMFXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor. J Biol Chem. 2000;275:22986–22994.[PubMed][Google Scholar]
  • 4. Grino PB, Griffin JE, Wilson JDTestosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology. 1990;126:1165–1172.[PubMed][Google Scholar]
  • 5. Askew EB, Gampe RT, Stanley TB, Faggart JL, Wilson EMModulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. J Biol Chem. 2007;282:25801–25816.[Google Scholar]
  • 6. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RESteroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974;186:1213–1215.[PubMed][Google Scholar]
  • 7. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DWTissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest. 1993;92:903–910.[Google Scholar]
  • 8. Miller WL, Auchus RJThe molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32:81–151.[Google Scholar]
  • 9. Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJDisruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res. 2002;62:1008–1013.[PubMed][Google Scholar]
  • 10. Ponguta LA, Gregory CW, French FS, Wilson EMSite-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. J Biol Chem. 2008;283:20989–21001.[Google Scholar]
  • 11. Vis AN, Schröder FH. Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways. BJU Int. 2009;104:438–448.[PubMed]
  • 12. Gregory CW, Hamil KG, Kim D, Hall SH, Pretlow TG, Mohler JL, French FSAndrogen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. Cancer Res. 1998;58:5718–5724.[PubMed][Google Scholar]
  • 13. Veldscholte J, Ris-Stalpers C, Kuiper GG, Jenster G, Berrevoets C, Claassen E, et al 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. 1990;173:534–540.[PubMed][Google Scholar]
  • 14. Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332:1393–1398.[PubMed][Google Scholar]
  • 15. Tan J, Sharief Y, Hamil KG, Gregory CW, Zang DY, Sar M, et al Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol. 1997;11:450–459.[PubMed][Google Scholar]
  • 16. Chang CY, Walther PJ, McDonnell DPGlucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer. Cancer Res. 2001;61:8712–8717.[PubMed][Google Scholar]
  • 17. Mohler JL, Gregory CW, Ford OH, Kim D, Weaver CM, Petrusz P, et al The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440–448.[PubMed][Google Scholar]
  • 18. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JLTestosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11:4653–4657.[PubMed][Google Scholar]
  • 19. Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, et al Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67:5033–5041.[PubMed][Google Scholar]
  • 20. Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407–6415.[PubMed][Google Scholar]
  • 21. Lih FB, Titus MA, Mohler JL, Tomer KBAtmospheric pressure photoionization tandem mass spectrometry of androgens in prostate cancer. Anal Chem. 2010;82:6000–6007.[Google Scholar]
  • 22. Leon CG, Locke JA, Adomat HH, Etinger SL, Twiddy AL, Neumann RD, 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. 2010;70:390–400.[PubMed][Google Scholar]
  • 23. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215–224.[PubMed][Google Scholar]
  • 24. Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:1192–1202.[PubMed][Google Scholar]
  • 25. Andriole G, Lieber M, Smith J, Soloway M, Schroeder F, Kadmon D, et al Treatment with finasteride following radical prostatectomy for prostate cancer. Urology. 1995;45:491–497.[PubMed][Google Scholar]
  • 26. Shah SK, Trump DL, Sartor O, Tan W, Wilding GE, Mohler JLPhase II study of dutasteride for recurrent prostate cancer during androgen deprivation therapy. J Urology. 2009;181:621–626.[Google Scholar]
  • 27. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, Wilson EMA mechanism for androgen receptor mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res. 2001;61:4315–4319.[PubMed][Google Scholar]
  • 28. Karpf AR, Bai S, James SR, Mohler JL, Wilson EMIncreased expression of androgen receptor coregulator MAGE-11 in prostate cancer by DNA hypomethylation and cyclic AMP. Mol Cancer Res. 2009;7:523–535.[Google Scholar]
  • 29. Russell DW, Wilson JDSteroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25–61.[PubMed][Google Scholar]
  • 30. Walsh PC, Wilson JDThe induction of prostatic hypertrophy in the dog with androstanediol. J Clin Invest. 1976;57:1093–1097.[Google Scholar]
  • 31. Shaw G, Renfree MB, Leihy MW, Shackleton CH, Roitman E, Wilson JDProstate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol. Proc Natl Acad Sci USA. 2000;97:12256–12259.[Google Scholar]
  • 32. Shaw G, Fenelon J, Sichlau M, Auchus RJ, Wilson JD, Renfree MBRole of the alternate pathway of dihydrotestosterone formation in virilization of the Wolffian ducts of the tammar wallaby, Macropus eugenii. Endocrinology. 2006;147:2368–2373.[PubMed][Google Scholar]
  • 33. Bauman DR, Steckelbroeck S, Williams MV, Peehl DM, Penning TMIdentification of the major oxidative 3alpha-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][Google Scholar]
  • 34. Bartsch W, Klein H, Schiemann U, Bauer HW, Voigt KDEnzymes of androgen formation and degradation in the human prostate. Ann NY Acad Sci. 1990;595:53–66.[PubMed][Google Scholar]
  • 35. Span PN, Sweep CG, Benraad TJ, Smals AG3 Alpha-hydroxysteroid oxidoreductase activities in dihydrotestosterone degradation and back-formation in rat prostate and epididymis. J Steroid Biochem Mol Biol. 1996;58:319–324.[PubMed][Google Scholar]
  • 36. Penning TM, Steckelbroeck S, Bauman DR, Miller MW, Jin Y, Peehl DM, et al Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors. Mol Cell Endocrinol. 2006;248:182–191.[PubMed][Google Scholar]
  • 37. Penning TM, Bauman DR, Jin Y, Rizner TLIdentification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor. Mol Cell Endocrinol. 2007;265–266:77–82.[Google Scholar]
  • 38. Cooper WC, Jin Y, Penning TMElucidation of a complete kinetic mechanism for a mammalian hydroxysteroid dehydrogenase (HSD) and identification of all enzyme forms on the reaction coordinate: the example of rat liver 3alpha-HSD (AKR1C9) J Biol Chem. 2007;282:33484–38493.[PubMed][Google Scholar]
  • 39. Biswas MG, Russell DWExpression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate. J Biol Chem. 1997;272:15959–15966.[PubMed][Google Scholar]
  • 40. He XY, Yang YZ, Peehl DM, Lauderdale A, Schulz H, Yang SYOxidative 3alpha-hydroxysteroid dehydrogenase activity of human type 10 17beta-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol. 2003;87:191–198.[PubMed][Google Scholar]
  • 41. Balk SP. Increased expression of genes converting adrenal androgens to testosterone in castration-recurrent prostate cancer. In: Tindall D, Mohler JL, editors. Androgen action in prostate cancer. New York: Springer; 2009. pp. 123–139. [PubMed]
  • 42. Penning TMNew frontiers in androgen biosynthesis and metabolism. Curr Opin Endocrinol Diabetes Obes. 2010;17:233–239.[Google Scholar]
  • 43. Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB, Wilson EMActivation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 2011;71:1486–1496.[Google Scholar]
  • 44. Frederiksen DW, Wilson JDPartial characterization of the nuclear reduced nicotinamide adenine dinucleotide phosphate: delta 4-3-ketosteroid 5 alpha-oxidoreductase of rat prostate. J Biol Chem. 1971;246:2584–2593.[PubMed][Google Scholar]
  • 45. Thomas LN, Douglas RC, Lazier CB, Gupta R, Norman RW, Murphy PR, et al Levels of 5alpha-reductase type 1 and type 2 are increased in localized high grade compared to low grade prostate cancer. J Urol. 2008;179:147–151.[PubMed][Google Scholar]
  • 46. Titus MA, Gregory CW, Ford OH, Schell MJ, Maygarden SJ, Mohler JLSteroid 5alpha-reductase isozymes I and II in recurrent prostate cancer. Clin Cancer Res. 2005;11:4365–4371.[PubMed][Google Scholar]
  • 47. Yokoi H, Tsuruo Y, Miyamoto T, Ishimura KSteroid 5 alpha-reductase type 1 immunolocalized in the adrenal gland of normal, gonadectomized, and sex hormone-supplemented rats. Histochem Cell Biol. 1998;109:127–134.[PubMed][Google Scholar]
  • 48. Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y, Nakagawa HNovel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Sci. 2008;99:81–86.[PubMed][Google Scholar]
  • 49. Godoy A, Kawinski E, Li Y, Oka D, Alexiev B, Azzouni F, et al 5α-reductase type 3 expression in human benign and malignant tissues: A comparative analysis during prostate cancer progression. Prostate. 2010 Epub ahead of print. [Google Scholar]
  • 50. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, et al Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815–2825.[PubMed][Google Scholar]
  • 51. O'Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason M, et al Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer. 2004;90:2317–2325.[Google Scholar]
  • 52. Attard G, Cooper CS, de Bono JSSteroid hormone receptors in prostate cancer: a hard habit to break? Cancer Cell. 2009;16:458–462.[PubMed][Google Scholar]
  • 53. Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E, et al Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742–3748.[Google Scholar]
  • 54. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583) J Clin Oncol. 2004;22:1025–1033.[PubMed][Google Scholar]
  • 55. Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O, et al Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 2006;10:309–319.[PubMed][Google Scholar]
  • 56. Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, et al Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA. 1998;95:5246–5250.[Google Scholar]
  • 57. Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, et al Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69:16–22.[Google Scholar]
  • 58. Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJSplicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008;68:5469–5477.[Google Scholar]
  • 59. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 2010;120:2715–2730.[Google Scholar]
  • 60. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, et al Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc Natl Acad Sci USA. 2010;107:16759–16765.[Google Scholar]
  • 61. Gregory CW, He B, Wilson EMThe putative androgen receptor-A form results from in vitro proteolysis. J Mol Endocrinol. 2001;27:309–319.[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.