Summary Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation leading to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in the conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC.

In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.hormonal therapy | 5-alpha-androstanedione | tumor metabolism | abiraterone acetate | hormone resistance

Summary Background HSD3B1(1245A>C) has been mechanistically linked to castration-resistant prostate cancer by encoding an altered enzyme that augments dihydrotestosterone synthesis. We hypothesized that men inheriting the HSD3B1(1245C) allele would exhibit resistance to androgen deprivation therapy (ADT). Methods We determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. Patients who received postoperative adjuvant or salvage radiotherapy were eligible, provided they had residual active disease as reflected by continued increase in their PSA after treatment. We analyzed progression-free survival (PFS; primary endpoint), distant metastasis-free survival (DMFS), and overall survival (OS) according to HSD3B1 genotype. Multivariable analyses were performed to assess the independent predictive value of HSD3B1 genotype on outcomes. Results were externally validated in two additional cohorts, including a second post-prostatectomy biochemical failure cohort as well as a metastatic cohort. There was no age limit for eligibility in the primary or validation cohorts. Findings The study included 443 patients: 118 in the primary cohort, 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median PFS diminished as a function of the number of variant alleles inherited: 6.6 years in homozygous wild-type men (95% CI, 3.8 to not reached); 4.1 years in heterozygotes (95% CI, 3.0 to 5.5); and 2.5 years in homozygous variant men (95% CI, 0.7 to not reached); P=0.011. Median DMFS likewise decreased according to the number of variant alleles inherited: 9.1 years (95% CI, 7.4 to not reached); 6.8 years (95% CI, 4.3 to 7.4); and 3.6 years (95% CI, 1.0 to 7.3), respectively; P=0.014. Finally, OS diminished with the number of variant alleles inherited: 5-year and 10-year OS 82% (95% CI, 69 to 94) and 55% (95% CI, 35 to 75) in homozygous wild-type men; 74% (95% CI, 62 to 85) and 35% (95% CI, 21 to 49) in heterozygotes; and 58% (95% CI, 30 to 86) and 0% in homozygous variant men; P=0.0064. On multivariable analysis, the hazard ratio (HR) for progression was 1.6 for men with at least one variant allele (95% CI, 1.0 to 2.7; P=0.074), which compared favorably with Gleason score (HR 1.3 for Gleason score 8–10 vs. 6–7; 95% CI 0.8 to 2.0; P=0.31), though neither factor reached statistical significance with the small sample size. The impact of homozygous variant genotype on metastasis (HR 2.8; 95% CI, 1.1 to 6.7; P=0.025) and death (HR 3.5; 95% CI 1.3 to 9.5; P=0.013) was maintained on multivariable analysis. Findings in the external cohorts independently validated the impact of HSD3B1(1245C) on outcomes. Interpretation Inheritance of the HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. Our findings nominate HSD3B1 as a powerful genetic biomarker capable of distinguishing men who are a priori ...

Prostate cancer is driven by androgen stimulation of the androgen receptor (AR). The next-generation AR antagonist, enzalutamide, prolongs survival, but resistance and lethal disease eventually prevail. Emerging data suggest that the glucocorticoid receptor (GR) is upregulated in this context, stimulating expression of AR-target genes that permit continued growth despite AR blockade. However, countering this mechanism by administration of GR antagonists is problematic because GR is essential for life. We show that enzalutamide treatment in human models of prostate cancer and patient tissues is accompanied by a ubiquitin E3-ligase, AMFR, mediating loss of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which otherwise inactivates cortisol, sustaining tumor cortisol concentrations to stimulate GR and enzalutamide resistance. Remarkably, reinstatement of 11β-HSD2 expression, or AMFR loss, reverses enzalutamide resistance in mouse xenograft tumors. Together, these findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents a requirement for systemic GR ablation.DOI: http://dx.doi.org/10.7554/eLife.20183.001

Purpose: Treatment with abiraterone (abi) acetate prolongs survival in castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to upregulation of steroidogenic enzymes and/or other mechanisms that sustain dihydrotestosterone (DHT) synthesis, which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. On the basis of the 3b-hydroxyl, D 5 -structure, we hypothesized that abi also inhibits 3b-hydroxysteroid dehydrogenase/isomerase (3bHSD), which is absolutely required for DHT synthesis in CRPC, regardless of origins or routes of synthesis. Experimental Design: We tested the effects of abi on 3bHSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo.Results: Abi inhibits recombinant 3bHSD activity in vitro and endogenous 3bHSD activity in LNCaP and LAPC4 cells, including conversion ofandrogen receptor nuclear translocation, expression of androgen receptor-responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA. Abi also blocks conversion of D 5 -androstenediol to testosterone by 3bHSD. Abi inhibits 3bHSD1 and 3bHSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC 50 value of less than 1 mmol/L in CRPC cell lines; inhibits androgen receptor nuclear translocation; expression of TMPRSS2, prostate-specific antigen, and FKBP5; and decreases CRPC xenograft growth in DHEA-supplemented mice. Conclusions: We conclude that abi inhibits 3bHSD-mediated conversion of DHEA to active androgens in CRPC. This second mode of action might be exploited to reverse resistance to CYP17A1 inhibition at the standard abi dose by dose-escalation or simply by administration with food to increase drug exposure. Clin Cancer Res; 18(13);

Altered DAB2IP gene expression often detected in prostate cancer (PCa) is due to epigenetic silencing. In this study, we unveil a new mechanism leading to the loss of DAB2IP protein; an oncogenic S-phase kinase-associated protein-2 (Skp2) as E3 ubiquitin ligase plays a key regulator in DAB2IP degradation. In order to unveil the role of Skp2 in the turnover of DAB2IP protein, both prostate cell lines and prostate cancer specimens with a variety of molecular and cell biologic techniques were employed. We demonstrated that DAB2IP is regulated by Skp2-mediated proteasome degradation in the prostate cell lines. Further analyses identified the N-terminal DAB2IP containing the ubiquitination site. Immunohistochemical study exhibited an inverse correlation between DAB2IP and Skp2 protein expression in the prostate cancer tissue microarray. In contrast, DAB2IP can suppress Skp2 protein expression is mediated through Akt signaling. The reciprocal regulation between DAB2IP and Skp2 can impact on the growth of PCa cells. This reciprocal regulation between DAB2IP and Skp2 protein represents a unique homeostatic balance between tumor suppressor and oncoprotein in normal prostate epithelia, which is apparently altered in cancer cells. The outcome of this study has identified new potential targets for developing new therapeutic strategy for PCa.

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