Skip to main content
SpringerLink
Log in
Book cover

Androgen Action in Prostate Cancer pp 141–154Cite as

Androgen-Metabolic Genes in Prostate Cancer Predisposition and Progression

  • Chapter
  • First Online:

  • 811 Accesses

Abstract

Prostate cancer is the most common nonskin cancer and the second leading cause of cancer deaths among men in most Western countries, including the US and Australia. Despite its high morbidity and mortality, the etiology of prostate cancer remains elusive. Longstanding clinical and compelling laboratory data suggest a role for androgens in prostate carcinogenesis. This chapter reviews the status of research on hormones, particularly androgens, and prostate cancer and focuses first on hormone-related genetic loci in constitutional (“germline”) DNA. This set of loci has been investigated in a number of studies to date that will undoubtedly expand further. These data provide insights into susceptibility for prostate cancer. This review next explores the emerging field of somatic mutations in tumor (“somatic”) DNA in androgen-metabolic genes, especially the androgen receptor and the type II steroid 5α-reductase. Integration of these forthcoming data with those on susceptibility may provide novel insights into the etiology and progression of prostate cancer. These lines of investigation may lead to the presymptomatic identification of high-risk individuals for active disease prevention, diagnostic improvements in affected men and personalized treatment. Current and future data on individual markers and genes should be integrated into a comprehensive, pathway-based picture that includes constitutional DNA (for prostate cancer susceptibility) and tumor DNA (for disease progression). These efforts may lead to a comprehensive genetically based risk and progression assessment algorithm.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Akalu, A., Elmajian, D. A., Highshaw, R. A., Nichols, P. W., Reichardt, J. K. V.: Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5α-reductase during prostate cancer progression. Journal of Urology,161: 1355–1358, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Bangsi, D., Zhou, J., Sun, Y., Patel, N. P., Darga, L. L., Heilbrun, L. K., Powell, I. J., Severson, R. K., Everson, R. B.: Impact of a genetic variant in CYP3A4 on risk and clinical presentation of prostate cancer among white and African-American men. Urologic Oncology, 24: 21–27, 2006.

    PubMed  CAS  Google Scholar 

  • Belanger,A., Hum,D. W., Beaulieu,M., Levesque,E., Guillemette,C., Tchernof,A., Belanger,G., Turgeon,D., Dubois,S.: Characterization and regulation of UDP-glucuronosyltransferases in steroid target tissues. The Journal of Steroid Biochemistry and Molecular Biology, 65:301–310, 1998.

    Article  PubMed  CAS  Google Scholar 

  • Carey, A. H., Waterworth, D., Patel, K., White, D., Little, J., Novelli, P., et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Human Molecular Genetics, 3: 1873–1876, 1994.

    Article  PubMed  CAS  Google Scholar 

  • Chamberlain, N. L., Driver, E. D., Miesfeld, R. L.: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Research, 22: 3181–3186, 1994.

    Article  PubMed  CAS  Google Scholar 

  • Chang, B. L., Zheng, S. L., Hawkins, G. A., Isaacs, S. D., Wiley, K. E., Turner, A., Carpten, J. D., Bleecker, E. R., Walsh, P. C., Trent, J. M., Meyers, D. A., Isaacs, W. B., Xu, J.: Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility. Cancer Research, 62: 1784–1789, 2002.

    PubMed  CAS  Google Scholar 

  • Chokkalingam,A. P., Stanczyk,F. Z., Reichardt,J. K. V., HsingA. W.: Molecular Epidemiology of Prostate Cancer: Hormone-Related Genetic Loci. Frontiers in Bioscience,12:3436–60, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Chouinard, S., Barbier, O., Belanger, A.: UDP-glucuronosyltransferase (UGT)2B15 and UGT2B17 enzymes are major determinants of the androgen response in prostate cancer LNCaP cells. The Journal of Biological Chemistry, 282: 33466–33474, 2007; [Epub ahead of print]

    Article  PubMed  CAS  Google Scholar 

  • Coffey, D. S.: The Molecular Biology of the Prostate. In: Prostate Diseases (Lepor, H. and Lawson, R. K., eds.), WB Saunders, Philadelphia, PA, 28–56, 1993.

    Google Scholar 

  • Culig, Z., Hobisch, A., Hittmair, A., Peterziel, H., Radmayr, C., Bartsch, G., et al. Hyperactive androgen receptor in prostate cancer: what does it mean for new therapy concepts?Histology and Histopathology, 12: 781–786, 1997.

    PubMed  CAS  Google Scholar 

  • Dalhoff,K., Buus Jensen,K., Enghusen Poulsen,H.: Cancer and molecular biomarkers of phase 2. Methods Enzymology, 400: 618–627, 2005.

    Article  CAS  Google Scholar 

  • Edwards, A., Hammond, H. A., Jin, L., Caskey, C. T., Chakraborty, R.: Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics, 12: 241–253, 1992.

    Article  PubMed  CAS  Google Scholar 

  • Freedland, S. J., Giovannucci, E., and Platz, E. A.: Are findings from studies of obesity and prostate cancer really in conflict?Cancer Causes Control, 17: 5–9, 2006.

    Article  Google Scholar 

  • Fung,K. M., Samara,E. N., Wong,C., Metwalli,A., Krlin,R., Bane,B., Liu,C. Z., Yang,J. T., Pitha,J. V., Culkin,D. J., Kropp,B. P., Penning,T. M., Lin,H. K.: Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Endocrine Related-Cancer, 13: 169–180, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Gallagher,C. J., Kadlubar,F. F., Muscat,J. E., Ambrosone,C. B., Lang,N. P., Lazarus,P.: The UGT2B17 gene deletion polymorphism and risk of prostate cancer A case-control study in Caucasians. Cancer Detection and Prevention, 31: 310–315, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Harkonen, P. L. and Makela, S. I.: Role of estrogens in development of prostate cancer. The Journal of Steroid Biochemistry and Molecular Biology, 92: 297–305, 2004.

    Article  PubMed  Google Scholar 

  • He,D, Falany,C. N.: Inhibition of SULT2B1b expression alters effects of 3beta-hydroxysteroids on cell proliferation and steroid hormone receptor expression in human LNCaP prostate cancer cells. Prostate, 67: 1318–1329, 2007.

    Article  PubMed  CAS  Google Scholar 

  • He,D., Meloche,C. A., Dumas,N. A., Frost,A. R., Falany,C. N.: Different subcellular localization of sulphotransferase 2B1b in human placenta and prostate. Biochemistry Journal379: 533–40, 2004.

    Article  CAS  Google Scholar 

  • Hoffmann, R., Happle, R.: Current understanding of androgenetic alopecia. Part I: etiopathogenesis. European Journal of Dermatology, 10: 319–327, 2000.

    PubMed  CAS  Google Scholar 

  • Hsing, A. W., Reichardt, J. K., and Stanczyk, F. Z.: Hormones and prostate cancer: current perspectives and future directions. Prostate, 52: 213–235, 2002a.

    Article  CAS  Google Scholar 

  • Hsing, A. W., Chokkalingam, A. P., Gao, Y. T., Wu, G., Wang, X., Deng, J. et al: Polymorphic CAG/CAA repeat length in the AIB1/SRC-3 gene and prostate cancer risk: a population-based case-control study. Cancer Epidemiology Biomarkers and Prevention, 11: 337–341, 2002b.

    CAS  Google Scholar 

  • Huggins, C. and Hodges, C. V.: Studies on prostatic cancer: Effect of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Research, 1: 293–297, 1941.

    CAS  Google Scholar 

  • Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., Smigal, C. and Thun, M. J.: Cancer statistics, 2007. CA: A Cancer Journal for Clinicians, 57: 43–66, 2007.

    Article  Google Scholar 

  • Ji,Q., Chang,L., VanDenBerg,D., Stanczyk,F. Z., Stolz,A.: Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism. Prostate,2003; 54: 275–289. Erratum in: Prostate, 66: 445, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Ji,Q., Chang,L., Stanczyk,F. Z., Ookhtens,M., Sherrod,A., Stolz,A.: Impaired dihydrotestosterone catabolism in human prostate cancer: critical role of AKR1C2 as a pre-receptor regulator of androgen receptor signaling. Cancer Research, 67: 1361–1369, 2007.

    Article  PubMed  CAS  Google Scholar 

  • Kraft, P., Pharoah, P., Chanock, S. J., Albanes, D., Kolonel, L. N., Hayes, R. B., Altshuler, D., Andriole, G., Berg, C., et al. Genetic variation in the HSD17B1 gene and risk of prostate cancer. PLoS Genet, 1: e68, 2005.

    Article  PubMed  Google Scholar 

  • Makridakis, N. M., Ross, R. K., Pike, M. C., Crocitto, L. E., Kolonel, L. N., Pearce, C. L., Henderson, B. E., J. K.Reichardt: Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet, 354: 975–978, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Makridakis, N. M., di SalleE., Reichardt, J. K.: Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics, 10: 407–413, 2000.

    Article  PubMed  CAS  Google Scholar 

  • Makridakis,N. M., Akalu,A., Reichardt,J. K. V.: Identification and Characterization of Somatic Steroid 5α-Reductase (SRD5A2) Mutations in Human Prostate Cancer Tissue, Oncogene23: 7399–7405, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Makridakis, N. M., Buchanan, G., Tilley, W., Reichardt, J. K. V.: Androgen Metabolic Genes in Prostate Cancer Predisposition and Progression, Frontiers in Bioscience, 10: 2899–2903, 2005.

    Article  Google Scholar 

  • Margiotti, K., Kim, E., Pearce, C. L., E.Spera, G.Novelli, J. K.Reichardt: Association of the G289S single nucleotide polymorphism in the HSD17B3 gene with prostate cancer in Italian men. Prostate, 53: 65–68, 2002.

    Article  PubMed  CAS  Google Scholar 

  • Noble, R. L.: The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Research, 37: 1929–1933, 1977.

    PubMed  CAS  Google Scholar 

  • Ntais,C., Polycarpou,A., Ioannidis,J. P.: SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiology Biomarkers and Prevention, 12: 618–624, 2003.

    CAS  Google Scholar 

  • Park,J., Chen,L., Shade,K., Lazarus,P., Seigne,J., Patterson,S., Helal,M., Pow-Sang,J.: Asp85tyr polymorphism in the udp-glucuronosyltransferase (UGT) 2B15 gene and the risk of prostate cancer. Journal of Urology, 171(6 Pt 1): 2484–2488, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Park,J., Chen,L., Ratnashinge,L., Sellers,T. A., Tanner,J. P., Lee,J. H., Dossett,N., Lang,N., Kadlubar,F. F., Ambrosone,C. B., Zachariah,B., Heysek,R. V., Patterson,S., Pow-Sang,J.: Deletion polymorphism of UDP-glucuronosyltransferase 2B17 and risk of prostate cancer in African American and Caucasian men. Cancer Epidemiology Biomarkers and Prevention, 15: 1473–1478, 2006.

    Article  CAS  Google Scholar 

  • Pasquali, R., Casimirri, F., Cantobelli, S., Melchionda, N., Morselli Labate, A. M., Fabbri, R.et al: Effect of obesity and body fat distribution on sex hormones and insulin in men. Metabolism, 40: 101–104, 1991.

    Article  PubMed  CAS  Google Scholar 

  • Penning,T. M., Jin,Y., Steckelbroeck,S., Lanisnik Rizner,T., Lewis,M.: Structure-function of human 3 alpha-hydroxysteroid dehydrogenases: genes and proteins. Molecular and Cellular Endocrinology, 215: 63–72, 2004.

    Article  PubMed  CAS  Google Scholar 

  • Platz, E. A., Giovannucci, E., Brown, M., Cieluch, C., Shepard, T. F., Stampfer, M. J., et al. Amplified in breast cancer-1 glutamine repeat and prostate cancer risk. Prostate Journal, 2: 27–32, 2000.

    Article  Google Scholar 

  • Rebbeck, T. R., Jaffe, J. M., Walker, A. H., Wein, A. J., Malkowicz, S. B.: Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. Journal of National Cancer Institute, 90: 1225–1229, 1998.

    Article  CAS  Google Scholar 

  • Reichardt,J. K. V.: Unexpected biochemical and pharmacogenetic consequences of SNPs and haplotypes: A cautionary tale for human molecular genetics and epidemiology. Genomics,88: 673–674, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Richie, J. P.: Anti-androgens and other hormonal therapies for prostate cancer. Urology, 54: 15–18, 1999.

    Article  PubMed  CAS  Google Scholar 

  • Ross, R. K., Bernstein, L., Lobo, R. A., Shimizu, H., Stanczyk, F. Z.,Pike, M. C. & Henderson, B. E.: 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet, 339: 887–889, 1992.

    Article  PubMed  CAS  Google Scholar 

  • Ross, R. K., Pike, M. C., Coetzee, G. A., Reichardt, J. K., Yu, M. C., Feigelson, H., et al: Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Research, 58: 4497–4504, 1998.

    PubMed  CAS  Google Scholar 

  • Sawaya, M. E., Shalita, A. R.: Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. Journal of Cutaneous Medicine and Surgery, 3: 9–15, 1998.

    PubMed  CAS  Google Scholar 

  • Thompson, I. M., Goodman, P. J., Tangen, C. M., Lucia, M. S., Miller, G. J., Ford, L. G., Lieber, M. M., Cespedes, R. D., Atkins, J. N., Lippman, S. M., Carlin, S. M., Ryan, A., Szczepanek, C. M., Crowley, J. J., Coltman, C. A.Jr.: The Influence of Finasteride on the Development of Prostate Cancer, New England Journal of Medicine, 349: 215–224, 2003.

    Article  PubMed  CAS  Google Scholar 

  • Wilborn, T. W., Lang, N. P., Smith, M., Meleth, S., Falany, C. N.: Association of SULT2A1 allelic variants with plasma adrenal androgens and prostate cancer in African American men. The Journal of Steroid Biochemistry and Molecular Biology, 99: 209–214, 2006.

    Article  PubMed  CAS  Google Scholar 

  • Yeh, S., Chang, C.: Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proceedings of the National Academy of Sciences of the United States of America, 93: 5517–5521, 1996.

    Article  PubMed  CAS  Google Scholar 

  • Zhao, X. Y. and Feldman, D.: The role of vitamin D in prostate cancer. Steroids, 66: 293–300, 2001.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by NCI grant P01 CA108964 (project 1) to JKVR who is also a Medical Foundation Fellow at the University of Sydney and by NIH Intramural Support (AWH).

Author information

Authors and Affiliations

  1. Plunkett Chair of Molecular Biology (Medicine), University of Sydney, Bosch Institute, Sydney, Camperdown, NSW, 2006, Australia

    Juergen K.V. Reichardt & Ann W. Hsing

Authors
  1. Juergen K.V. Reichardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann W. Hsing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juergen K.V. Reichardt .

Editor information

James Mohler Donald Tindall

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Reichardt, J.K., Hsing, A.W. (2009). Androgen-Metabolic Genes in Prostate Cancer Predisposition and Progression. In: Mohler, J., Tindall, D. (eds) Androgen Action in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69179-4_6

Download citation

Publish with us

Policies and ethics

Search

Navigation