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Beyond the Abstract - Androgen regulation of 5α-reductase isoenzymes in prostate cancer: Implications for prostate cancer prevention, by Jin Li, PhD, Christopher I. Amos, PhD, and Jeri Kim, MD

BERKELEY, CA (UroToday.com) -

Role of 5α-Reductase in Prostate Cancer Prevention

Multistep pathogenesis and a long latency period make prostate cancer a promising candidate for chemoprevention,[1] particularly because of androgen receptor (AR) signaling, a central signaling pathway in prostate cancer pathogenesis and progression.[2 In the prostate, circulating testosterone is converted to dihydrotestosterone (DHT) by 5α-reductase, and then both testosterone and DHT can bind to the AR, leading to AR activation and transcription of its broad-range downstream targeted genes. The dissociation rate between DHT and the AR is much lower than that between testosterone and the AR,[3, 4] making DHT the major androgen in AR signaling.

Because of the important role of 5α-reductase in converting testosterone to DHT, it has been considered a main target for prostate cancer prevention. Of the three different isoenzymes of 5α-reductase encoded by different genes, two, SRD5A1 and SRD5A2, have been well studied. Clinically used 5α-reductase inhibitors include finasteride, which inhibits the activity of SRD5A2,[5] and dutasteride, which inhibits both SRD5A1 and SRD5A2,[6] but it remains controversial whether such agents can inhibit the activity of SRD5A3.[7, 8] To identify these isoenzymes’ effects, investigators have undertaken several clinical trials.

bta kimThe Prostate Cancer Prevention Trial (PCPT) was a landmark study that enrolled 18,882 men who were at least 55 years old with prostate-specific antigen (PSA) levels ≤3.0 ng/mL and normal findings on a digital rectal examination (DRE).[9] These participants were randomly assigned to either finasteride or placebo for 7 years. The results showed that 18.4% of men treated with finasteride developed prostate cancer, compared with 24.4% of the men treated with placebo; thus, the men in the finasteride-treated group had a statistically significantly lower prevalence of prostate cancer (24.8%; p<0.001); however, high-grade tumors (Gleason grade ≥7) were more commonly detected among men in the finasteride group than in the placebo group (6.4% vs. 5.1%; p=0.005). Follow-up study of PCPT prostatectomy specimens by Pinsky et al.[10] determined that finasteride’s effect was statistically favorable, despite the detection of high-grade tumors; nevertheless, finasteride’s role in the development of high-grade tumors is still being debated, and the biologic mechanisms responsible for the increase in high-grade tumors remain to be defined to the satisfaction of all stakeholders. 

Another prostate cancer prevention trial, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which focused on the dual 5α-reductase inhibitor dutasteride, yielded a similar result.[11] This trial aimed to evaluate whether dutasteride could reduce prostate cancer risk among men with increased risk of prostate cancer. The 6729 men were followed for 4 years. At enrollment, they were 50–75 years old, they had PSA levels of 2.5–10.0 ng/mL, and their most recent prostate biopsy results were negative for prostate cancer.[11] The investigators found a 22.8% relative risk (RR) reduction (p<0.001). As in the PCPT, high-grade tumors with Gleason scores of 8–10 were detected in both arms of the REDUCE study during years 1 and 2 (dutasteride, 17 tumors: placebo, 18 tumors); however, differences became statistically significant during years 3 and 4 (dutasteride, 12; placebo, 1 [p=0.003]). Overall, for years 1-4, 29 tumors with Gleason scores of 8-10 were detected in the dutasteride group and 19 in the placebo group (p=0.15). Although the difference in the total number of high-grade tumors is not statistically significant and the researchers of the study attributed this difference to the removal of the 141 participants with tumors of Gleason scores 5–7, it remains possible that dutasteride was one of the causes of the difference. Furthermore, an independent reassessment of biopsy specimens from the REDUCE trial indicated a significantly increased risk for men with tumors of Gleason scores 8–10 in the dutasteride group (RR=2.06; 95% CI=1.13, 3.75).[12]

Some focus and appreciation of the complexity of findings from the two original studies may have been lost. Foremost, it should be recognized that the reductions achieved in prostate cancer risk in the PCPT and REDUCE trials were important because they represented statistically significant findings for prespecified primary end points. These reductions are no less important because they occurred predominantly in men with Gleason score 6 or less, especially inasmuch as it is known that diagnosis often prompts men to seek definitive therapy with its associated life quality–lowering side effects. In fact, PCPT investigators subsequently showed that 62% of those tumors detected with Gleason scores ≤6 met biopsy criteria for clinically significant disease.[13] The high-grade findings, on the other hand, represent secondary end points, which are vulnerable not only to sampling bias (because they are determined by biopsy) but also to the size-altering effects of 5α-reductase inhibitors on the prostate. Finally, detection bias may have contaminated both the reduction in low-grade tumors and the increase in high-grade tumors, producing underestimation of the former and overestimation of the latter.

The results of another important clinical trial examining prostate cancer, REDEEM (Reduction by Dutasteride of Clinical Progression Events in Expectant Management), were reported earlier this year.[14] The aim of the study, conducted in 302 men, was to evaluate whether dutasteride treatment has any effect on the progression of low-risk, localized prostate cancer. By the end of 3 years, data from 289 participants with one or more biopsies after baseline were analyzed. The results showed that 54 of 144 men (38%) in the dutasteride-treated group experienced either pathologic or therapeutic progression of prostate cancer, whereas 70 of 145 men (48%) in the placebo arm experienced progression, demonstrating a significant delay in prostate cancer progression (hazard ratio, 0.62; p=0.009, log-rank test). On the basis of this result, the researchers concluded that dutasteride could have beneficial effect for patients with low-risk prostate cancer who are under active surveillance. At least partially because of its short study period and its end point definition, REDEEM trial’s results have met skepticism and sparked argument.[15] The disease grade–dependent effects of the 5α-reductase inhibitors are noteworthy, and results from all of these clinical trials suggest that using 5α-reductase inhibitors to prevent prostate cancer may not be suitable for all men. Many clinical investigators have been intrigued by the PCPT and REDUCE trial results. With the aim of understanding the different response to the 5α-reductase inhibitor dutasteride, Mostaghel et al.[16] conducted a microarray gene expression study on microdissected normal prostate epithelial cells from patients with prostate cancer either left untreated or treated with two different dosages of dutasteride for 4 months before prostatectomy. Using 90 androgen-regulated genes, the authors were able to segregate the dutasteride-treated samples into two distinct groups designated by high or low AR gene activity. All of these dutasteride-treated samples, with only one exception, can also be classified into these two groups, simply on the basis of the abundance of AR mRNA. Their results prompted the authors to propose that patients may respond to 5α-reductase inhibitor therapy on the basis of the level of AR expression. Certainly the small sample size and the analysis confined to nonmalignant prostate tissue limit the impact of findings in this study.

Also intrigued by the clinical trial results, we investigated the androgen regulation of 5α-reductase.[17] Using prostate cell lines as model systems, we found that the expression of 5α-reductase varied across different cell lines. Furthermore, the mRNA level of each 5α-reductase isoenzyme in a given cell line changed differently in response to androgen; the expression of each of the three isoenzymes also responded to androgen treatment in a cell type–specific manner. In addition, we found that androgen regulates 5α-reductase transcription through the AR. Though owing to the experiment’s limitation we found no androgen response elements (AREs) on the promoter of SRD5A1 or SRD5A2, we did identify a negative ARE on the proximal promoter of SRD5A3. Our findings demonstrate that the main axis of AR signaling is subject to complicated self-regulation. Thus, we speculate that even though administration of finasteride or dutasteride may result in an overall reduction of the intraprostatic DHT level, AR signaling may undergo different modulation depending on the AR status, 5α-reductase genotypic variants, and different expression levels of 5α-reductase.

What further adds to the complexity is the different effects of testosterone and DHT in the regulation of AR signaling. The different effects of these two major male hormones lie not only in the disassociation rates with the AR but also in the regulation of downstream AR gene expression.[18] An early study by Lin and Chang [19] indicated that testosterone and DHT exhibit different effects on suppression of TDD5 gene expression. Compared with DHT, testosterone showed a faster and more remarkable effect on repression of TDD5 expression. Also, Avila et al.[20] compared male rats treated with castration or finasteride to intact control animals and found genes showing different mRNA levels in these conditions, suggesting that these genes are regulated differently by DHT and testosterone. Moreover, when Dadras et al. [21] treated castrated male rats for 7 days with either testosterone combined with finasteride or testosterone alone, they observed higher expression of genes likely to be responsible for prostate differentiation and growth inhibition in the combination–treated group than they did in those treated with testosterone alone. In the presence of finasteride, the intraprostatic testosterone level was kept high; in its absence, implanted testosterone was effectively converted to DHT. Therefore, their results actually suggest testosterone and DHT have different effects on prostate differentiation and proliferation.[18, 21]

Epidemiological studies also have been debating the associations between androgen levels and prostate cancer risk. Earlier studies suggested a positive association between testosterone level and prostate cancer risk,[22, 23] but no association for DHT and prostate cancer risk.[22] After examining baseline serum androgen levels and prostate cancer incidence among controls in the REDUCE trial, Muller et al. reported recently finding no overall association was found between baseline serum testosterone and prostate cancer risk, but they did identify a statistically significant positive association among men with low baseline testosterone (<10 nmol/l), suggesting a saturation model.[24] No association between DHT and prostate cancer risk was found overall or in stratified subgroups.[24] Though these findings need to be further validated, this study adds supporting evidence for the differential effects of testosterone and DHT. Unlike androgen-ablation therapy, finasteride or dutasteride treatment alters the testosterone:DHT ratio in the prostate; thus, each individual patient’s different testosterone:DHT ratio could also influence the effects of clinical treatment. In summary, 5α-reductase inhibitor administration may modulate AR signaling in singular ways, owing to the complexity of that signaling at various levels, and therefore different individuals receiving 5α-reductase inhibitor therapy may exhibit different effects.

Hence, using a combined treatment strategy may be necessary for prostate cancer prevention. The ongoing Therapy Assessed by Rising PSA (TARP) study,[25] which is designed to test the combined effect of dutasteride and bicalutamide against that of bicalutamide alone on disease progression in castration-resistant prostate cancer, may reveal the clinical effect of AR signaling blockade at multiple steps. Delineating efficient inhibition of AR signaling for prostate cancer prevention and treatment will require further, more extensive and translational studies and clinical investigation.

References:

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  2. Nacusi, L.P. and D.J. Tindall, Targeting 5alpha-reductase for prostate cancer prevention and treatment. Nat Rev Urol, 2011. 8(7): p. 378-84.
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  8. Yamana, K., F. Labrie, and V. Luu-The, Human type 3 5a-reductase is expressed in peripheral tissues at higher levels than type 1 and type 2 and its activity is potently inhibited by finasteride and dutasteride. Horm Mol Biol Clin Invest, 2010. 2(3): p. 293-9.
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  17. Li, J., et al., Androgen regulation of 5alpha-reductase isoenzymes in prostate cancer: implications for prostate cancer prevention. PLoS One, 2011. 6(12): p. e28840.
  18. Gupta, S., D. Shevrin, and Z. Wang, Improving Intermittent Androgen-Deprivation Therapy: OFF Cycle and the Role of Steroid 5α-Reductase Inhibitors. Androgen Action in Prostate Cancer, Springer New York, 2009: p. 187-204.
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  20. Avila, D.M., et al., Identification of genes expressed in the rat prostate that are modulated differently by castration and Finasteride treatment. J Endocrinol, 1998. 159(3): p. 403-11.
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  25. Sartor, O., et al., Dutasteride and bicalutamide in patients with hormone-refractory prostate cancer: the Therapy Assessed by Rising PSA (TARP) study rationale and design. Can J Urol, 2009. 16(5): p. 4806-12.

 

 

 Written by:

Jin Li, PhD, Christopher I. Amos, PhD, and Jeri Kim, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract. 

 

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