Androgen signaling is central to prostate cancer

Androgen signaling is central to prostate cancer development and progression. A milestone in progression of advanced prostate cancer when it transitions from endocrine-driven to paracrine- or intracrine-driven androgen signaling, with progressive complexities in steroid hormone biosynthesis and alterations of the androgen receptor (AR) (Logothetis et al., 2013). The PCPT, the first study to demonstrate that prostate cancer could be prevented or greatly delayed (Thompson et al., 2003), showed that men taking the type 2 5α-reductase steroid inhibitor finasteride had a relative reduction of 24.8% (P<0.001) in the 7-year period prevalence of prostate cancer compared with men taking the placebo, a reduction that increased to 30% on assessment of all men who were randomized (Thompson et al., 2013). Paradoxically, incidence of high-grade disease also significantly increased among men on finasteride. Although detection bias appeared, in part, to account for the increase in high-grade disease (Lucia et al., 2007), true induction of de novo high-grade disease could not be ruled out and, therefore, the drug was not granted FDA approval for prostate cancer risk reduction. The controversy notwithstanding, the PCPT\'s relevance was made clear in the Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial (Fleshner et al., 2012). In that study, 302 men with low-grade prostate cancer undergoing active surveillance received three years of treatment with dutasteride or placebo. Dutasteride was associated with a 38% decrease in the cancer detection rate on repeat biopsy at year 3 (Fleshner et al., 2012), supporting the hypothesis that, based on response to a 5α-reductase steroid inhibitor, localized prostate cancer could be dichotomized as either dependent on dihydrotestosterone (DHT) or as able to adapt to DHT depletion.
Materials and Methods
Funding and Nonfinancial Support
Results
Discussion This type of difference in cell proliferation was also observed in a study by Kosaka et al. (2014), who found that 5α-reductase inhibitors (5ARIs) reduced an indicator of cell proliferation—CDC6 mRNA—in the androgen-dependent LNCaP cell line but saw the proliferation marker increase in androgen-independent lines C4-2 and C4-2AT6, the last a castration-resistant prostate cancer. Interestingly, they found the reverse effect with DHT. Kosaka and colleagues concluded that 5ARIs might help accelerate ep4 to aggressive phenotypes in some prostate cancer types. Finally, our finding of lower AR expression in GG4 tumor areas after short-term finasteride exposure is in line with an emerging concept that reduced androgens in prostate tissues may over time lead to derepression of AR expression, which in turn deregulates AR function and downstream derepression of specific AR target genes normally repressed by androgens (Cai et al., 2011). These gene activities may lead to stochastic activation of oncogenic signaling that promotes the development of aggressive prostate cancer. Wang et al. (2009), for example, have shown in mice that castration-resistant Nkx3-1 (CARN) cells—rare luminal epithelial stem cells that survive androgen withdrawal—can give rise to basal, luminal, and neuroendocrine cells after restoration of androgen. Others have shown these cells also regenerate ducts and self-renew (Leong et al., 2008). By deleting the tumor-suppressing gene Pten in these cells, Wang et al. further demonstrated that high-grade prostatic intraepithelial neoplasia, and carcinoma rapidly formed in the Pten-free system, with CARN cells serving as cells of origin after androgen-mediated renewal. It wasn\'t that we expected, based on the long-standing presumption of step-wise progression, that finasteride would be found responsible for the high-grade disease detected by others; in fact, it was an effort to examine the nexus of transition and begin to characterize the molecular processes. Our study\'s design provided an ideal opportunity to back-validate markers of apoptosis (e.g., cleaved caspase 3) and cellular proliferation (e.g., Ki-67), which are commonly used in this class of chemopreventive agents as surrogates for chemoprevention efficacy in short-term, phase II clinical trials in prostate cancer and other cancers (Parnes et al., 2013). After short-term exposure to finasteride, expression of the apoptotic factor cleaved caspase 3 in GG3 and GG4 tumor areas was significantly increased, demonstrating, as shown in the PCPT, preventive efficacy. Additionally, within both arms, levels of cleaved caspase 3 were significantly lower in GG4 tumors than in GG3 tumors. Ananthanarayanan et al. (2006) and Ummanni et al. (2010) independently found that, compared with levels of activated caspase 3 in normal prostate epithelium, levels of activated caspase 3 in untreated prostate cancer from radical prostatectomy specimens were significantly lower. Evidence that Ki-67 was modulated by finasteride was not detected during the study.