title: Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility.
abstract: The prostate is an androgen-regulated organ, which has led to long-standing interest in the role of androgens in prostate carcinogenesis. Although evidence of a hormonal etiology for prostate cancer is strong, it is almost entirely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormones. The international and racial-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that whereas environmental factors are likely to be important, genetic factors might also play a central role in determining prostate cancer risk. We are developing a polygenic model of prostate carcinogenesis focused around a series of genes involved in androgen biosynthesis and androgen activation, transport, and metabolism in the prostate. In this developing model, we have initially targeted four genes based on three main criteria: (a) all encode products that play important roles in inducing androgen stimulation in the prostate; (b) all are polymorphic; and (c) all show substantial allelic variation in the polymorphic marker among the racial-ethnic groups of greatest interest in terms of prostate cancer risk. In addition to studying how the polymorphic markers of interest are related to prostate cancer development within and between racial-ethnic groups, we are concurrently evaluating whether genotypic variations correlate in the anticipated direction with biochemical parameters in vitro and in vivo. We summarize the development of this model and the state of knowledge related to each of the genes comprising the current model. We discuss the extent to which the current model can explain demographic variation in prostate cancer risk as well as the potential for future expansion of the model to incorporate environmental risk factors as well as additional genes. The model, when fully developed, can potentially provide a basis for targeting populations for screening interventions and/or preventive strategies aimed at the multigene products or at the genes themselves.
authors.affiliation: Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles 90033-0800, USA. ross_r@froggy.hsc.usc.edu
authors.forename: R K
authors.initials: RK
authors.lastname: Ross
authors.forename: M C
authors.initials: MC
authors.lastname: Pike
authors.forename: G A
authors.initials: GA
authors.lastname: Coetzee
authors.forename: J K
authors.initials: JK
authors.lastname: Reichardt
authors.forename: M C
authors.initials: MC
authors.lastname: Yu
authors.forename: H
authors.initials: H
authors.lastname: Feigelson
authors.forename: F Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.forename: L N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: B E
authors.initials: BE
authors.lastname: Henderson
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000728:Androgens / Q000378:metabolism*; D042944:Cholestenone 5 alpha-Reductase; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008957:Models, Genetic; D010088:Oxidoreductases / Q000235:genetics; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D010088:Oxidoreductases; D015096:3-Hydroxysteroid Dehydrogenases; D013254:Steroid 17-alpha-Hydroxylase; D042944:Cholestenone 5 alpha-Reductase