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  • Findings conflict regarding the influence of ARIs on apoptos

    2018-11-14

    Findings conflict regarding the influence of 5ARIs on apoptosis. Bass et al. (2009) showed no effect on caspase 3 in a randomized, placebo-controlled, presurgical 30-day finasteride intervention in localized prostate cancer (N=22 in each arm). However, results of two dutasteride studies, both using terminal deoxynucleotidyl transferase dUTP nicked-end labeling, indicated effects, but findings were contradictory. Andriole et al. (2004), in a double-blind, randomized placebo-controlled trial, reported higher apoptosis levels in 46 men with clinically organ-confined prostate cancer treated with dutasteride or placebo for 6–10weeks before prostatectomy. In contrast, Gleave et al. (2006) reported a significant decrease in apoptosis when dutasteride was compared with placebo for four months before prostatectomy. This further supports the notion that the molecular effects of 5ARIs depend on exposure duration. In gssg to our results, findings of Thomas et al. (2008) in untreated tumors indicate expression of SRD5A2, the target of finasteride, is higher in high-grade than in low-grade localized disease. Their earlier work had indicated in part that SRD5A2 expression rose as prostate cancer progressed (Thomas et al., 2005). Differences between study populations may explain the discordance, inasmuch as Thomas et al. examined GG3, GG4, and GG5 components from cancer overall (GSs of 5–8, GSs of 7–9, and GSs of 8–10, respectively), whereas expression we studied was in tumor foci with a narrow range of Gleason scores. Although we detected no change in the estrone or estradiol ligands of ER, estrogen has been shown by others to be important in prostate carcinogenesis and progression (Weihua et al., 2002). In early prostate cancer in the context of prostate cancer prevention with finasteride (Mak et al., 2010), 3β-adiol, a metabolite of DHT and a ligand of ERβ, may be important in cross-talk between AR and ER signaling. Furthermore, the biological significance of ER signaling in persistent low- and high-grade cancers warrants further investigation. Ours is one of few studies in early prostate cancer to consider the time it takes for response to therapy to be reflected in gene expression, but it has been studied in more advanced prostate cancers. Although AR expression four months following androgen deprivation therapy in a neoadjuvant setting before radical prostatectomy was not increased in hormone-naive high-grade cancers (Efstathiou et al., 2013), an increase in expression and a commensurate AR gene copy number increase have been frequently observed in castration-resistant prostate cancer (Scher et al., 2004), and expression further increased after only eight weeks of abiraterone (Efstathiou et al., 2012). Our findings emphasize the need to understand the temporal relationships of finasteride-induced molecular changes and their biological and clinical implications. Overall, finasteride\'s differential modulation of AR in GG3 versus GG4 areas of tumor suggests grade-associated differences in AR signaling in early prostate cancer. The heterogeneity of AR signaling networks has been recognized for a long time. In work with cell lines (Li et al., 2011), we found dramatic variability characterized AR signaling: complicated self-regulation controlled the central axis of AR signaling, 5α-reductase expression varied across cell lines, each cell line varied in response to androgen, androgen controlled 5α-reductase transcription through the AR pathway, and expression of each of the three 5α-reductase enzymes was cell-type specific. Confining the study to the largest focus of the peripheral zone, thereby limiting any bias introduced by the tumor heterogeneity inherent in the multifocal and multizonal nature of prostate cancer, reinforces confidence in the findings. Perhaps high-grade tumors are more sensitive than low-grade tumors to the disequilibrium of testosterone and DHT caused by finasteride or dutasteride, and, as a consequence, AR expression paradoxically decreases as a short-term adaptation. A corollary may be that low-grade tumors are more dependent than high-grade tumors on DHT. If so, this may be the mechanism whereby finasteride and dutasteride reduced the likelihood of finding low-grade tumors on biopsy in other trials (Thompson et al., 2003; Andriole et al., 2010).