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Androgen and Prostate Cancer: Is the Hypothesis Dead?

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Androgen and Prostate Cancer: Is the Hypothesis Dead? 2525 Hypothesis/Commentary Androgen and Prostate Cancer: Is the Hypothesis Dead? Ann W. Hsing,1 Lisa W. Chu,1,2 and Frank Z. Stanczyk3,4 1Division of Cancer Epidemiology and Genetics, and 2Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, Maryland; and 3Departments of Obstetrics and Gynecology, and 4Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California Abstract Data fromanimal,clinical, and prevention studies hypothesis; rather, it underscores the importance of a support the role of androgen in prostate cancer growth, better understanding of androgen action within the proliferation, and progression. However, results serum- prostate, including the relationship between tissue and based epidemiologic studies in humans have been serum levels of androgen. In this commentary, we inconclusive. Part of the inconsistency in these find- explain why circulating levels of testosterone may not ings stems from differences in study population, assay reflect androgen action in the prostate and why tissue accuracy, intraperson variation, and limited sample levels of androgen, in particular dihydrotestosterone, size. Recently, data froma large pooled analysis of 18 and the androgen receptor and its coregulators are prospective studies (3,886 cases and 6,438 healthy critical to androgen action in the prostate and should be controls) showed no association between serumandro- incorporated in future studies. It is timely to integrate gen and prostate cancer risk. It is not surprising that the systemthinking into our research and use an interdis- pooled analysis did not find a positive link between ciplinary approach that involves different disciplines, circulating levels of total testosterone and prostate including epidemiology, endocrinology, pathology, cancer risk because, individually, few of the 18 studies and molecular biology, to help dissect the complex included in the pooled analysis reported a substantial interplay between sex steroids and genetic and lifestyle positive association. The null result, however, does factors in prostate cancer etiology. (Cancer Epidemiol not pronounce a death sentence for the androgen Biomarkers Prev 2008;17(10):2525–30) Introduction In a recent article, Roddam et al. and the Endogenous channel our energy and resources in research on Hormone and Prostate Cancer Collaborative Group (1) nonandrogen risk factors? Definitely not! In our view, reported no association between blood levels of total the null finding on total serum testosterone from the testosterone and prostate cancer risk based on pooled pooled analysis underscores the importance of a better analysis of 18 prospective studies. The pooled analysis understanding of the relationship between tissue and included 3,886 men withprostate cancer and 6,438 serum levels of androgens to clarify the role of androgens controls. It is the largest serum-based study with the in prostate cancer etiology. most elegant and comprehensive analysis to date to test a central hypothesis in prostate cancer etiology. It is not surprising that the pooled analysis did not find a positive The Origin of the Androgen Hypothesis link between circulating levels of total testosterone and prostate cancer risk because, individually, few of To appreciate fully the importance of tissue levels of the 18 studies included in the pooled analysis reported androgen and the possibility that serum testosterone may a substantial positive association. not reflect androgen action within the prostate, we need How do we interpret this null result? Does this mean to understand the biosynthesis and metabolism of that, as suggested by the accompanying editorial (2), the androgens, androgen signaling within the prostate, and androgen hypothesis, the most biologically plausible the origin of the testosterone hypothesis in prostate and widely tested hypothesis for prostate cancer, is cancer. In 1941, Huggins and Hodges (3) showed that dead? Is it time to abandon the androgen hypothesis and marked reductions in serum testosterone levels by castration or high-dose estrogen therapy resulted in the regression of metastatic prostate cancer. This seminal Received 5/16/08; revised 6/27/08; accepted 7/7/08. work (which won them a Nobel prize in 1966) and Grant support: Intramural ResearchProgram of theNIH, National Cancer Institute. subsequent studies led to the hypothesis that higher Note: A.W. Hsing is a member of the Endogenous Hormone and Prostate Cancer Collaborative Group. testosterone levels cause enhanced growth of prostate Requests for reprints: Ann W. Hsing, Division of Cancer Epidemiology and Genetics, cancer and resulted in the use of androgen ablation National Cancer Institute, Executive Plaza South5024, MSC 7234, 6120 Executive therapy for the management of prostate cancer (4). The Boulevard, Bethesda, Maryland 20892. Phone: 301-496-1691; Fax: 301-402-0916. E-mail: [email protected] androgen hypothesis was further supported by the fact Copyright D 2008 American Association for Cancer Research. that the introduction of supplementary testosterone can doi:10.1158/1055-9965.EPI-08-0448 induce prostate cancer in rat models (5). Cancer Epidemiol Biomarkers Prev 2008;17(10). October 2008 Downloaded from cebp.aacrjournals.org on September 24, 2021. © 2008 American Association for Cancer Research. 2526 Androgen and Prostate Cancer Androgen Metabolismin the Prostate Despite the critical role of tissue 5a-dihydrotestoster- one in prostate growthand proliferation, data on the In men, testosterone is synthesized primarily in the testes relationship between tissue androgens and prostate and, to some extent, in the adrenal glands. In the cancer are limited. In addition, little is known about the circulation, about 45% of the total testosterone binds to correlation between serum and tissue levels of androgens sex hormone–binding globulin (SHBG), about 50% binds in healthy men, partly because of the difficulty in loosely to albumin, and <4% is unbound (free testoster- obtaining freshnormal prostate tissue, thecomplexity one; refs. 6-8). Within the prostate, testosterone is related to tissue processing for hormone assays, and converted irreversibly to 5a-dihydrotestosterone by the tissue heterogeneity (13). Our group is currently devel- enzyme 5a-reductase type II, encoded by the SRD5A2 oping assays to overcome some of these limitations as gene (Fig. 1; refs. 6–8). Although testosterone and 5a- well as assessing androgen profiles in normal, hyper- dihydrotestosterone can bind the androgen receptor plastic, and tumor tissue. In most epidemiologic studies, (Fig. 1), androgen receptor has a higher affinity for the serum level of 3a-androstanediol glucuronide, a 5a-dihydrotestosterone than for testosterone, and andro- terminal metabolite of testosterone, is used as a surrogate gen receptor is more transcriptionally active when bound marker for tissue androgen levels. It should be noted that to 5a-dihydrotestosterone. The activity of the 5a- circulating levels of 3a-androstanediol glucuronide re- dihydrotestosterone–androgen receptor transcription flect activities of both5 a-reductase types I and II, with factor complex is modulated by translocation to the cell type I expressed more abundantly in extraprostatic nucleus and the binding of various androgen receptor tissues such as the skin and type II in the prostate (14). coregulators, including coactivators and corepressors The concentration of 3a-androstanediol glucuronide in (Fig. 1; refs. 9-11). The 5a-dihydrotestosterone–androgen serum correlates well with5 a-reductase activity in receptor–coregulator complex can translocate to the cell genital skin (6, 7, 15, 16); recent data from studies of nucleus, where it activates transcription of genes with finasteride, a 5a-reductase type II inhibitor, show that hormone-responsive elements in their promoters to serum levels of 5a-dihydrotestosterone and 3a- induce androgen signaling (12). Thus, androgenic action androstanediol glucuronide decrease concomitantly in in the prostate is determined by a multitude of factors, treated men, suggesting that serum levels of 3a-andros- including concentration of androgen receptor and its tanediol glucuronide may reflect predominantly the coregulators as well as tissue levels of 5a-dihydrotestos- activity of the steroid 5a-reductase type II (6, 17). terone. 5a-dihydrotestosterone levels in the prostate are Several lines of evidence also support the importance determined by (a) testosterone metabolism, (b) metabo- of tissue androgens. For example, data from the Prostate lism of androstenedione via 5a-androstanedione, and (c) Cancer Prevention Trial showed that the use of finas- 5a-dihydrotestosterone inactivation by its reduction to teride reduces the risk for prostate cancer by 25% (18), 3a-or3h-androstanediol (Fig. 1), a process that is rever- suggesting that 5a-reductase type II activity (and sible. Both5a -dihydrotestosterone metabolites can be therefore testosterone metabolism within the prostate) conjugated into 3a-or3h-androstanediol glucuronide, plays a role in prostate cancer, which in turn supports the an irreversible process. important role of tissue 5a-dihydrotestosterone in pros- Figure 1. Androgen metabolism in the pros- tate. Cancer Epidemiol Biomarkers Prev 2008;17(10). October 2008 Downloaded from cebp.aacrjournals.org on September 24, 2021. © 2008 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 2527 tate carcinogenesis. Previous studies have shown that
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