Androgen Metabolism and Prostate Cancer: Establishing a Model of Genetic Susceptibility

Abstract

The prostate is an androgen-regulated organ, which has led to longstanding 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 genetic factors 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, transport and metabolism. We have begun to develop this model by utilizing sequence variants to study how polymorphic markers in two genes (SRD5A2 and AR) are related to prostate cancer risk within and between racial-ethnic groups. We are now collaborating with the Whitehead Institute/MIT, Center for Genome Research, to screen for single nucleotide polymorphisms in additional genes relevant to the androgen pathway and prostate cell growth. The model when fully developed can potentially provide a basis for targeting populations for screening interventions and for implementing primary preventive strategies.

U.S. dietary exposures to heterocyclic amines*

“…Detailed histological evidence of multifocality and genetic heterogeneity within excised prostate tumors supports this hypothesis (Ruijter et al, 1996;Macintosh et al, 1998;Djavan et al, 1999 ). Testosterone -and insulin -related hormones are known to regulate prostate cell proliferation, and racial ± ethnic differences in genetic markers that modulate the levels and /or effectiveness of these hormones may help explain observed racial± ethnic differences in PC occurrence (Ross et al, 1998;Pettaway, 1999;Signorello et al, 1999 ). Nevertheless, exposure to environmental carcinogenic mutagens such as dietary PhIP may contribute to PC risk by acting independently from or perhaps even synergistically with underlying genetic susceptibilities to hormonal PC promotion.…”

A missense substitution A49T in the steroid 5-alpha-reductase gene (SRD5A2) is not associated with prostate cancer in Finland

“…A germline mis-sense substitution (A49T) leads to a variant SRD5A2 protein, which has a 5-fold higher in vitro V max than the wild-type protein (Ross et al, 1998;Makridakis et al, 1999). The A49T variant was recently associated with 2.5 to 3.28-fold increased risk of prostate cancer (PC) in African-American and Hispanic men (Makridakis et al, 1999).…”

“…A TA-dinucleotide repeat polymorphism at the 3′ UTR of SRD5A2 (Davis and Russell, 1993;Reichardt et al, 1995;Kantoff et al, 1997) and a valine to leucine substitution at codon 89 (Makridakis et al, 1997;Febbo et al, 1999;Lunn et al, 1999) have not been found to be associated with prostate cancer. A third polymorphism, alanine to threonine substitution at codon 49 (A49T) results in a variant 5-α-reductase enzyme with a V max of about 5 times that of the wild enzyme (Ross et al, 1998;Makridakis et al, 1999). Makridakis et al (1999) recently reported that the A49T variant was more common among 216 African-American and 172 Hispanic prostate cancer patients than in the corresponding ethically matched controls.…”

The role of candidate genetic polymorphisms in the etiology of prostate cancer

“…20,21 These differences are suggestive that these genes may explain a proportion of ethnic differences in prostate cancer risk and therefore be important in the etiology of prostate cancer. Functional differences in level of activity of genetic variants have been reported for SRD5A2 22,24 and AR. 9 These functional differences could be associated with prostate cancer risk.…”