Androgen Prostate Cancer Research Articles

Abstract 5229: Expression and regulation of chondroitin sulfate in prostate cancer

Abstract Increased levels of chondroitin sulfate (CS) glycosaminoglycans (GAGs) in prostate cancer (PC) have been observed for more than three decades. In 1984, De Klerk et al. noted that hyperplastic and cancerous prostate contained elevated levels of CS while other GAGs, like heparin sulfate (HS), were decreased. Chondroitin sulfate-modified proteoglycans (CSPGs), such as versican or tomoregulin (TENB2), have been promoted as PC progression markers. They have been associated with cell attachment to the matrix, the metastatic phenotype, disease progression, and androgen independence. Functionally, pericellular enrichment of CSPGs in the PC microenvironment promotes cell motility. Our team has discovered that human tumors display high levels of a specific highly sulfate type of CS normally restricted to placental and fetal tissue compartment. This "oncofetal" CS (ofCS) GAG can be conveniently detected and targeted using recombinant CS-binding VAR2CSA (rVAR2) lectins, derived from the malaria parasite Plasmodium falciparum. Recently, we identified chondroitin sulfate biosynthesis as being controlled by androgens in PC, modulating expression of the CHST11 and CHST13 carbon-4 GalNAc sulfotransferases. We established that these enzymes are under direct control of the androgen receptor (AR), regulating synthesis of the cancer-associated ofCS-modification on CSPGs. Glycosylation has a key role in many important biologic processes in cancer including cell differentiation. We identified CHST11 to be highly increased in high-risk neuroendocrine prostate cancer (NEPC) both in vitro, in vivo, and in situ. Moreover, cells that expressed neuroendocrine markers showed higher level of sulfation and ofCS. Our work reveals that alterations in GAG signatures regulated by AR might be responsible for progression neuroendocrine differentiation in prostate cancer. The prostate is an abundant secretor of PGs, and tumor-specific alterations in GAG signatures such as ofCS therefore constitute an untapped reservoir of potential biomarkers to be exploited as therapeutic targets. Citation Format: Nader Al Nakouzi, Chris Kedong Wang, Irina Nelepcu, Coralie Crouzit, Noushin Nabavi, Amal Almami, Htoo Zarni Oo, Thomas Mandel Clausen, Tobias Gustavsson, Ali Salanti, Mads Daugaard. Expression and regulation of chondroitin sulfate in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5229.

Abstract 1314: A prostate cancer androgen receptor variant gene network with prognostic and therapeutic value identified using integrated systems analyses

Abstract Constitutively active androgen receptor (AR) splice variants such as AR-V7 represent a well-established mechanism of disease progression to castration-resistant prostate cancer (CRPC), the incurable form of PC. These AR variants lack the carboxyl-terminal ligand binding domain, the target of all approved drugs against AR. Consequently, a significant challenge is to identify novel therapeutic strategies that are effective against AR variants-expressing prostate tumors without requiring direct targeting of these variants, which is challenging due in part to the unstructured nature of the AR amino terminus. We used a multi-pronged, unbiased systems biology approach to identify downstream AR-V7-regulated hub genes that both drive cancer progression and feedback to enhance AR-V7 activity. Such genes likely encode prognostic markers as well as potential therapeutic targets acting within the AR-V7 network. Our systems biology approach utilized: 1) clinically relevant gene sets upregulated during human PC progression obtained by Weighted Gene-Co-expression Network Analysis (WGCNA); 2) an AR-V7 functional interactome from a high-throughput synthetic genetic array (SGA) screening in the yeast, Schizosaccharomyces pombe; and 3) PC cell AR-V7 transcriptome. We identified seven genes that were upregulated in human PC, functionally interacted with AR-V7 and were AR-V7 targets in PC. This gene set, composed of cell cycle and mitosis-regulating genes, not only encoded select proteins previously linked to PC, such as Cyclin B1 and Topoisomerase 2A (CCNB1 and TOP2A), but also proteins with little or no prior association with AR-V7 or PC. The seven genes comprised a signature that strongly correlated with patient Gleason score and predicted disease free-survival in large independent PC patient cohorts. In contrast, this gene set was not associated with survival metrics in other human cancers. Individual depletion of the expression of these genes decreased ligand-independent AR transcriptional activity and reduced CRPC cell proliferation. Furthermore, individual knock down of the members of the gene set affected the expression of the other members of the set indicative of the interrelationship of these genes. Consistent with CRPC dependence on these interrelated mitotic genes, combinatorial targeting of two of its members: TOP2A and CCNB1, led to a synergistic and selective inhibition of AR-driven CRPC cell proliferation but had no effect on non-tumorigenic prostate epithelial cells. This unbiased and novel gene discovery strategy, which is broadly applicable to other cancers, identified clinically-relevant interacting gene hubs forming the basis for both prognostic use and rational, combinatorial therapy for CRPC. Citation Format: Maria J. Martinez, Fiorella Magani, Eric R. Bray, Valeria Copello, Ning Zhao, Stephanie Peacock, David J. Wiley, Gennaro D'Urso, Kerry L. Burnstein. A prostate cancer androgen receptor variant gene network with prognostic and therapeutic value identified using integrated systems analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1314.

Role of OATP transporters in steroid uptake by prostate cancer cells in vivo.

BackgroundEpidemiologic and in vitro studies suggest SLCO-encoded OATP transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intra-tumor androgens. We have previously shown that castration resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated.MethodsWe sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated uptake of DHEAS, E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured uptake via administration of tritiated steroids to castrate mice bearing vector control or OATP1B1, 2B1 or 4A1-expressing xenografts. We treated tumor-bearing mice with DHEAS and testosterone at physiologically relevant levels and measured intra-tumor accumulation of administered steroids by mass spectrometry.ResultsOATP1B1 and 2B-expressing xenografts each showed a 3-fold increase in tritiated-DHEAS uptake vs vector controls (p=0.002 and p=0.036, respectively). At circulating DHEAS levels similar to those in abiraterone-treated men (~15ug/dL) OATP1B1 and 2B1-expressing xenografts showed a 3.9-fold (p=0.057) and 1.9-fold (p=0.048) increase in tumor accumulation of DHEAS, and a 1.6-fold (p=0.057) and 2.7-fold (p=0.095) increase in DHEA, respectively. At testosterone levels found in eugonadal men, a consistent effect of OATP1B1, 2B1 or 4A1 on testosterone uptake in vivo was not detected.ConclusionsOATP transporters measurably alter DHEAS uptake and intra-tumor androgen levels in prostate tumors in vivo, even at circulating androgen levels achieved in abiraterone-treated patients. These novel data emphasize the continued need to inhibit ligand-mediated AR signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.

Oestrogens and oestrogen receptors in prostate cancer.

The role of androgens in prostate cancer is obvious due to the fact that androgen signalling is the main regulator of prostate growth and function. Androgen deprivation therapy is a mainstay treatment for advanced prostate cancer. However, prostate cancer often becomes androgen-independent, which in consequence leads to lethal and incurable disease. In addition, oestrogens play a crucial role in prostate cancer, especially in elder men in whom the overall ratio of oestrogens to androgens is increasing. This review summarizes the current knowledge on molecular mechanisms through which oestrogens are involved in prostate cancer development. We focused on commonly alternated molecular signalling pathways contributing to tumourgenesis in prostate cancer.

Novel mechanism-based therapeutics for androgen axis blockade in castration-resistant prostate cancer.

Understanding the mechanisms by which castration-resistant prostate cancer (CRPC) progresses provides an opportunity to identify novel therapeutic strategies to treat this disease. This understanding has led to approaches to attack prostate cancer's androgen axis in unique ways. This review will examine the classes of novel therapies for androgen axis blockade in CRPC, with a particular focus on the unique characteristics of drugs in various stages of clinical development. The success of abiraterone and enzalutamide has stimulated multiple investigations into novel approaches to attack the androgen-signaling pathway. Drugs under development include cytochrome P17 inhibitors with 17,20-lyase specificity, androgen receptor antagonists that are active against mutated and constitutively active splice variant forms of the protein, androgen receptor degraders, and bromodomain/bromodomain extra-terminal inhibitors that prevent chromatin binding of activated receptors. The clinical development of several of these experimental agents is reviewed. Given the unique mechanisms of action for drugs in development, and the possibility that the novel agents may be active in the setting of common resistance mechanisms, treatment options for patients are likely to expand greatly in the coming years. Future studies should prioritize combinations of agents with unique mechanisms of action to optimize outcomes for patients, and should rely on precision-medicine approaches to target known molecular alterations.

Influence of Different Regimens of Prostate Cancer Androgen Deprivation on Metabolic Syndrome and Sexual Dysfunction

Androgen deprivation remains a golden standard therapy in advance Prostate cancer. Besides adequate suppression of the tumor growth, ADT causes temporary or even permanent sexual dysfunction along with the high risk of metabolic complications. In our prospective study we have included 56 patients with advanced forms of prostrate cancer and remained sexual activity whom were subjects to different regimens of ADT. The primary goal of our study was evaluation of the degree of metabolic complications and time to regain sexual activity using continuous and intermittent GnRH analogues therapy and sequential therapy with GnRH analogues and bicalutamide.

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression.

Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.

Abstract 3537: Stem-cell based selective delivery of alpha keto reductases for therapeutic targeting of residual androgens in prostate cancer

Abstract The twice as high incidence and mortality among African Americans (AA) compared to Caucasian Americans and other ethnic minorities remains elusive. The de novo synthesis of androgens by prostate tumors provides a significant survival advantage leading to outgrowth of castration resistant tumors. The “intracrine” production of androgens in the tumor microenvironment is greatly influenced by the synthesis of androgen metabolizing enzymes (AMEs) and the level of circulating hormones. Currently, targeting de novo synthesis of androgens in tumor microenvironment is singularly the toughest challenge presented to oncologists. Our present research attempts to identify and exploit the key players among the AMEs for targeting the backdoor pathway of DHT synthesis in castration resistant prostate cancer (CRPC). Comparative analysis of gene expression of AMEs in microdissected cells versus the adjacent normal tissue revealed AKR1C4 to be the most promising candidate for targeting the backdoor pathway in DHT synthesis. Existing literature supports this view since Type 1 3a-HSD enzyme has been shown to readily oxidize testosterone to Δ4-androstene-3, 17-dione in a substrate dependent reaction. Our analysis using recombinant AKR1C4 induced cytotoxicity and apoptosis in androgen dependent PC cells in vitro. Next, using a lentivirus construct, we genetically engineered tumor-tropic adipose-derived stem cells (ASCs) to express and secreted AKR1C14 (mouse homolog of AKR1C4). The results showed that ASCs are capable of expressing the enzyme, which can catabolize DHT in vitro and induce apoptosis in androgen dependent prostate cancer cells as shown by DHT Elisa, psPSA reporter assays and cytotoxicity and survival assays. Our current research plan is to examine the efficacy of tumor-tropic AKR1C14-expressing ASCs in targeting and inhibiting prostate metastatic growth in an animal model system. Citation Format: Manish Ranjan, Zakaria Abd Elmageed, Hogyoung Kim, Amrita Datta, Nobel Bhasin, Steven E. Braun, Debasis Mondal, Asim B. Abdel-Mageed. Stem-cell based selective delivery of alpha keto reductases for therapeutic targeting of residual androgens in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3537. doi:10.1158/1538-7445.AM2015-3537

Androgen-Induced TMPRSS2 Activates Matriptase and Promotes Extracellular Matrix Degradation, Prostate Cancer Cell Invasion, Tumor Growth, and Metastasis

Dysregulation of androgen signaling and pericellular proteolysis is necessary for prostate cancer progression, but the links between them are still obscure. In this study, we show how the membrane-anchored serine protease TMPRSS2 stimulates a proteolytic cascade that mediates androgen-induced prostate cancer cell invasion, tumor growth, and metastasis. We found that matriptase serves as a substrate for TMPRSS2 in mediating this proinvasive action of androgens in prostate cancer. Further, we determined that higher levels of TMPRSS2 expression correlate with higher levels of matriptase activation in prostate cancer tissues. Lastly, we found that the ability of TMPRSS2 to promote prostate cancer tumor growth and metastasis was associated with increased matriptase activation and enhanced degradation of extracellular matrix nidogen-1 and laminin β1 in tumor xenografts. In summary, our results establish that TMPRSS2 promotes the growth, invasion, and metastasis of prostate cancer cells via matriptase activation and extracellular matrix disruption, with implications to target these two proteases as a strategy to treat prostate cancer.

From bench to bedside: bipolar androgen therapy in a pilot clinical study.

Prostate cancer remains a leading cause of cancer death in Europe and the United States and is an emerging problem in Asia despite significant improvements in available treatments over the last few decades. Androgen deprivation therapy (ADT) has been the core treatment of advance-staged disease since the discovery of prostate cancer's androgen dependence in 1941 by Huggins et al.1 Options for initial medical treatment include gonadotropin-releasing hormone analogues such as leuprolide (LHRH agonist) and degarelix (LHRH antagonist) and androgen receptor (AR) binding agents such as bicalutamide. Although most patients will initially respond to either surgical or medical castration, there is almost always progression to castration-resistant prostate cancer (CRPC) necessitating treatment with more novel agents.2 However, even drugs such as abiraterone and enzalutamide, two next-generation agents used commonly in metastatic CRPC, have failed to demonstrate persistent efficacy in most patients.34

Abstract B15: Bone marrow stromal cell-secreted inflammatory cytokines promote treatment resistance and survival of prostate cancer cells

Abstract It is well established that prostate cancer (PCa) cells hone to, adapt, and thrive in the bone. Importantly, bone metastases are found in over 80% of PCa deaths. Therefore, it is imperative to elucidate and characterize the molecular mechanisms that enable PCa cells to thrive in the bone and resist conventional PCa therapies, such as hormone ablation or anti-androgens. We found that the HS-5 bone marrow stromal cell (BMSC) line, a secretory BMSC line that can support hematopoietic stem cell growth, secretes paracrine factors that induce apoptosis in PCa cells. However a subpopulation of the PCa cells can survive the BMSC-induced death. The surviving PCa subpopulation differentiates into a neuronal morphology and looses androgen receptor (AR) expression, reminiscent of treatment-resistant neuroendocrine PCa. Ideally, the loss of AR would induce PCa cell death; however we observe a concomitant increase in the autophagy-related cell survival protein, p62/SQSTM1, and induction of cytoprotective autophagy. Furthermore, we find that interleukin-1 beta (IL-1β) and IL-6, inflammatory cytokine secreted by HS-5 BMSCs, are sufficient to promote PCa neuronal morphology, reduce AR accumulation, upregulate p62/SQSTM1 levels, and induce autophagy. In addition, genetic silencing of p62/SQSTM1 causes PCa cell death and pharmacological inhibition of cytokine or autophagy signaling attenuates PCa neuroendocrine differentiation. Thus, our PCa-bone marrow stromal cell model suggests that PCa cells can co-opt the immune system in the bone microenvironment leading to PCa androgen independence, treatment resistance, and survival in the bone. Furthermore, our data suggests that inhibiting inflammatory cytokine signaling and/or the autophagy process are rational strategies to combat PCa bone metastasis. Citation Format: Megan Chang, Micaela Morgado, Viral Patel, Michael Gwede, Mary Cindy Farach-Carson, Nikki Delk. Bone marrow stromal cell-secreted inflammatory cytokines promote treatment resistance and survival of prostate cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B15. doi:10.1158/1538-7445.CHTME14-B15

Update on systemic therapy for advance prostate cancer

In 1942, Huggins and Hodges published data establishing the role of androgens in prostate cancer by showing that inhibition of androgens lead to regression of advanced prostate cancer. Androgen deprivation remains the mainstay of treatment for metastatic prostate cancer or situations that are not amenable to local therapy. Androgen deprivation or castration takes place by either medical or surgical means. Clinically, this is demonstrated by a testosterone level o50 ng/mL. Surgical castration is an efficient way to abruptly remove the source of androgens and is a viable option for some men.

In vitro modeling of HER2-targeting therapy in disseminated prostate cancer.

Prostate cancer (PCa) is the most common cancer type among men. Treatments against advanced PCa are limited and in many cases only palliative. In a later, androgent independent, stage of PCa androgen receptors can be activated without interaction with ligand, i.e., by receptors of tyrosine kinase (RTK) family in the outlaw pathway. Human epidermal growth factor receptors HER2 and EGFR belong to RTK-family. HER2 is one of the main actors in the outlaw pathway with EGFR as the preferable heterodimerizing partner. We hypothesized that information on HER2 expression in advanced PCa could be useful for selection of patients for anti-RTK therapy and monitoring of therapy response. A panel of PCa cell lines (LNCap, PC3, DU-145) was subjected to a 8-week treatment using drugs influencing the RTK: trastuzumab(anti‑HER2), 17-DMAG (Hsp90 inhibitor), alone or in combination, and their HER2 and EGFR expressions were compared with non-treated cells. Treatment with trastuzumab decreased proliferation of LNCap and DU-145 cell lines, while 17-DMAG and trastuzumab/17‑DMAG combination affected all three cell lines. HER2 expression was significantly increased in PC3 cells, the most resistant cell line. On the contrary, in responding cells (LNCap and DU-145) HER2 expression decreased, accompanied by increased EGFR expression. However, additional treatment of cells with cetuximab (anti‑EGFR) did not give any additive effect to trastuzumab. In this study the response to anti-RTK therapy proved to vary between different PCa cell lines. We have demonstrated that RTK targeting treatments may affect the phenotypic profile of PCa tumor cells that correlates with therapy outcome. Observation of such changes during treatment could be used for monitoring and an improved therapy outcome.

Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling

Early clinical studies suggested infiltrating T cells might be associated with poor outcomes in prostate cancer (PCa) patients. The detailed mechanisms how T cells contribute to PCa progression, however, remained unclear. Here, we found PCa cells have a better capacity to recruit more CD4(+) T cells than the surrounding normal prostate cells via secreting more chemokines-CXCL9. The consequences of more recruited CD4(+) T cells to PCa might then lead to enhance PCa cell invasion. Mechanism dissection revealed that infiltrating CD4(+) T cells might function through the modulation of FGF11→miRNA-541 signals to suppress PCa androgen receptor (AR) signals. The suppressed AR signals might then alter the MMP9 signals to promote the PCa cell invasion. Importantly, suppressed AR signals via AR-siRNA or anti-androgen Enzalutamide in PCa cells also enhanced the recruitment of T cells and the consequences of this positive feed back regulation could then enhance the PCa cell invasion. Targeting these newly identified signals via FGF11-siRNA, miRNA-541 inhibitor or MMP9 inhibitor all led to partially reverse the enhanced PCa cell invasion. Results from in vivo mouse models also confirmed the in vitro cell lines in co-culture studies. Together, these results concluded that infiltrating CD4(+) T cells could promote PCa metastasis via modulation of FGF11→miRNA-541→AR→MMP9 signaling. Targeting these newly identified signals may provide us a new potential therapeutic approach to better battle PCa metastasis.

Importance of 5α-Reductase Gene Polymorphisms on Circulating and Intraprostatic Androgens in Prostate Cancer

Polymorphisms in the genes SRD5A1 and SRD5A2 encoding androgen biosynthetic 5α-reductase enzymes have been associated with an altered risk of biochemical recurrence after radical prostatectomy in localized prostate cancer. To gain potential insights into SRD5A biologic effects, we examined the relationship between SRD5A prognostic markers and endogenous sex-steroid levels measured by mass spectrometry in plasma samples and corresponding prostatic tissues of patients with prostate cancer. We report that five of the seven SRD5A markers differentially affect sex-steroid profiles of dihydrotestosterone and its metabolites in both the circulation and prostatic tissues of patients with prostate cancer. Remarkably, a 32% increase in intraprostatic testosterone levels was observed in the presence of the high-risk SRD5A rs2208532 polymorphism. Moreover, SRD5A2 markers were associated predominantly with circulating levels of inactive glucuronides. Indeed, the rs12470143 SRD5A2 protective allele was associated with high circulating androstane-3α, 17β-diol-17-glucuronide (3α-diol-17G) levels as opposed to lower levels of both 3α-diol-17G and androsterone-glucuronide observed with the rs2208532 SRD5A2 risk allele. Moreover, SRD5A2 rs676033 and rs523349 (V89L) risk variants, in strong linkage disequilibrium, were associated with higher circulating levels of 3α-diol-3G. The SRD5A2 rs676033 variant further correlated with enhanced intraprostatic exposure to 5α-reduced steroids (dihydrotestosterone and its metabolite 3β-diol). Similarly, the SRD5A1 rs166050C risk variant was associated with greater prostatic exposure to androsterone, whereas no association was noted with circulating steroids. Our data support the association of 5α-reductase germline polymorphisms with the hormonal milieu in patients with prostate cancer. Further studies are needed to evaluate if these variants influence 5α-reductase inhibitor efficacy.

Regulation of PBX3 expression by androgen and Let-7d in prostate cancer

BackgroundThe pre-leukemia transcription factor 3 (PBX) is part of the PBX family of transcription factors, which is known to regulate genes involved in differentiation of urogenital organs and steroidogenesis. This is of interest with regard to prostate cancer progression as regulation of steroidogenesis is one of the mechanisms involved in the development of castration-resistant prostate cancer. In light of this we wanted to investigate the possible involvement of androgen regulation of PBX3 expression in prostate cancer.ResultsIn this study, we show that PBX3 is post-transcriptionally regulated by androgen in prostate cancer cells and that the effect might be independent of the androgen receptor. Furthermore, PBX3 was identified as a target of Let-7d, an androgen regulated microRNA. Let-7d was down-regulated in malignant compared to benign prostate tissue, whereas up-regulation of PBX3 expression was observed.ConclusionsWe demonstrate that PBX3 is up-regulated in prostate cancer and post- transcriptionally regulated by androgen through Let-7d.

The major role of androgens in prostate cancer and the need for more efficient blockade

Although improvements in surgery and radiotherapy have also occurred, National Cancer Institute data from 2.1 million patients with cancer in the USA between 1975 and 1995 have led to the conclusion that “cancer-fighting drugs improved survival rates, especially for cancer of the prostate, where drug innovations have been the greatest” [1]. In prostate cancer, the most important drugs have been gonadotropinreleasing hormone (GnRH) agonists [2] and pure anti-androgens permitting the administration of a pure anti-androgen combined with medical or surgical castration (combined androgen blockade [CAB]), at the start of treatment [3]. However, despite significant improvements in diagnosis and treatment, prostate cancer remains the second most common cause of death after lung cancer in American men.

Steroid up-regulation of FKBP51 and its role in hormone signaling

FK506 binding protein 51 (FKBP51, FKBP5) functions as a co-chaperone for androgen, glucocorticoid, mineralocorticoid and progesterone receptors. The FKBP51 can act as an important determinant of the responses to steroids, especially to glucocorticoids in stress and mood disorders and androgens in prostate cancer, raising medical and pharmacological interests in the protein and its gene. Recent studies have revealed the molecular mechanisms by which the androgens and the glucocorticoids via their nuclear receptors elicit the robust up-regulation of the FKBP51 gene. Several polymorphisms in the FKBP51 gene have been associated with the mood disorders and differences in glucocorticoid sensitivity. The polymorphisms may contribute to the steroid up-regulation of the FKBP51 and thus influence the regulatory loops in steroid signaling.

Cyclin D1 Is a Selective Modifier of Androgen-dependent Signaling and Androgen Receptor Function

D-type cyclins regulate cellular outcomes in part through cyclin-dependent, kinase-independent mechanisms that modify transcription factor action, and recent in vivo studies showed that cyclin D1 associates with a large number of transcriptional regulators in cells of the retina and breast. Given the frequency of cyclin D1 alterations in cancer, it is imperative to delineate the molecular mechanisms by which cyclin D1 controls key transcription factor networks in human disease. Prostate cancer was used as a paradigm because this tumor type is reliant at all stages of the disease on androgen receptor (AR) signaling, and cyclin D1 has been shown to negatively modulate AR-dependent expression of prostate-specific antigen (KLK3/PSA). Strategies were employed to control cyclin D1 expression under conditions of hormone depletion, and the effect of cyclin D1 on subsequent androgen-dependent gene expression was determined using unbiased gene expression profiling. Modulating cyclin D1 conferred widespread effects on androgen signaling and revealed cyclin D1 to be a selective effector of hormone action. A subset of androgen-induced target genes, known to be directly regulated by AR, was strongly suppressed by cyclin D1. Analyses of AR occupancy at target gene regulatory loci of clinical relevance demonstrated that cyclin D1 limits AR residence after hormone stimulation. Together, these findings reveal a new function for cyclin D1 in controlling hormone-dependent transcriptional outcomes and demonstrate a pervasive role for cyclin D1 in regulating transcription factor dynamics.

Androgen action in prostate cancer.

Prostate cancer represents a major health problem in men worldwide. Androgens are required for the growth and maintenance of the prostate. Androgens act by binding to the androgen receptor (AR), a nuclear receptor transcription factor present in the prostate tissues. Most prostate tumors also retain their androgen dependence; therefore, androgen ablation is usually the preferred initial therapeutic approach for the treatment of advanced prostate cancer patients. This review summarizes the current information regarding the role of androgens in prostate cancer.