Androgen-Metabolic Genes in Prostate Cancer Predisposition and Progression
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.
KeywordsProstate Cancer Androgen Receptor Prostate Cancer Risk Androgen Receptor Gene HSD17B1 Gene
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).
- 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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
- 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.PubMedCrossRefGoogle 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.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.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.PubMedCrossRefGoogle 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.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.CrossRefGoogle 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.PubMedCrossRefGoogle Scholar