Nuclear Androgen Receptor Research Articles

Machine Learning Consensus To Predict the Binding to the Androgen Receptor within the CoMPARA Project.

The nuclear androgen receptor (AR) is one of the most relevant biological targets of Endocrine Disrupting Chemicals (EDCs), which produce adverse effects by interfering with hormonal regulation and endocrine system functioning. This paper describes novel in silico models to identify organic AR modulators in the context of the Collaborative Modeling Project of Androgen Receptor Activity (CoMPARA), coordinated by the National Center of Computational Toxicology (U.S. Environmental Protection Agency). The collaborative project involved 35 international research groups to prioritize the experimental tests of approximatively 40k compounds, based on the predictions provided by each participant. In this paper, we describe our machine learning approach to predict the binding to AR, which is based on a consensus of a multivariate Bernoulli Naive Bayes, a Random Forest, and N-Nearest Neighbor classification models. The approach was developed in compliance with the Organization of Economic Cooperation and Development (OECD) principles, trained on 1687 ToxCast molecules classified according to 11 in vitro assays, and further validated on a set of 3,882 external compounds. The models provided robust and reliable predictions and were used to gather novel data-driven insights on the structural features related to AR binding, agonism, and antagonism.

Variations in the adenohypophysis of the expression of proliferating cellular nuclear antigen, oestrogen and androgen receptors in relation to gonadal steroids during pregnancy of viscachas (Lagostomus maximus maximus)

Viscachas are native rodents of South America that present a long pregnancy of ~154 days. In this work, we analysed variations in the expression of proliferating cellular nuclear antigen, oestrogen and androgen receptors (ERα and AR) in pituitary pars distalis (PD) and pars tuberalis (PT) in relation to oestradiol and testosterone serum levels in non-pregnant and pregnant viscachas. In PD, cell proliferation increased with pregnancy and lactotrophs proliferated during mid-pregnancy (MP). ERα nuclear-immunoreactive cells (ERαn-ir) were maximal in late pregnancy and AR expression did not vary during pregnancy. In PT, cell proliferation and AR expression increased during pregnancy, but ERα expression was very scarce. The immunostaining pattern of receptors was different in PD and PT. The peak of serum oestradiol and testosterone occurred during MP. Our results suggest that cell proliferation and gonadal receptors might be differentially regulated in the pituitary by oestradiol and testosterone during viscacha pregnancy.

Coffee diterpenes kahweol acetate and cafestol synergistically inhibit the proliferation and migration of prostate cancer cells.

Coffee inhibits the progression of prostate cancer; however, the direct mechanism through which coffee acts on prostate cancer cells remains unclear. This study aimed to identify the key compounds of coffee that possess anti-cancer effects and to investigate their mechanisms of action. The anti-proliferation and anti-migration effects of six potentially active types of coffee compounds, including kahweol acetate, cafestol, caffeine, caffeic acid, chlorogenic acid, and trigonelline hydrochloride, were evaluated using LNCaP, LNCaP-SF, PC-3, and DU145 human prostate cancer cells. The synergistic effects of these compounds were also investigated. Apoptosis-related and epithelial-mesenchymal transition-related proteins, androgen receptor in whole cell and in nucleus, and chemokines were assessed. A xenograft study of SCID mice was performed to examine the in vivo effect of coffee compounds. Among the evaluated compounds, only kahweol acetate and cafestol inhibited the proliferation and migration of prostate cancer cells in a dose-dependent manner. The combination treatment involving kahweol acetate and cafestol synergistically inhibited proliferation and migration (combination index <1) with the induction of apoptosis, the inhibition of epithelial-mesenchymal transition, and decrease in androgen receptor, resulting in the reduction of nuclear androgen receptor in androgen receptor-positive cells. Moreover, kahweol acetate and cafestol downregulated CCR2 and CCR5 without an increase in their ligands, CCL2 and CCL5. The xenograft study showed that oral administration of kahweol acetate and cafestol significantly inhibited tumor growth. Kahweol acetate and cafestol synergistically inhibit the progression of prostate cancer. These coffee compounds may be novel therapeutic candidates for prostate cancer.

Regional Variation in Androgen Receptor Expression and Biomechanical Properties May Contribute to Cryptorchidism Susceptibility in the LE/orl Rat.

Background: The process of testicular descent requires androgen and insulin-like 3, hormones secreted by fetal Leydig cells. Knowledge concerning distinct and common functions of these hormones in regulating development of the fetal gubernaculum remains limited and/or conflicting. The current studies were designed to better define characteristics of androgen receptor (AR) expression, function and regulation, as well as the biomechanical properties of normal and cryptorchid gubernaculum during fetal development.Methods: We studied fetal gubernacula from Long Evans outbred (LE/wt) rats and an inbred (LE/orl) strain with an inherited form of cryptorchidism associated with an AR signaling defect. Gubernacular cells or whole organs obtained from LE/wt and LE/orl fetal gubernacula underwent AR immunostaining and quantitative image analysis. The effects of dihydrotestosterone (DHT) on AR expression, muscle fiber morphology, hyaluronan (HA) levels and glycosaminoglycan (GAG) content were measured in LE/wt gubernacula. Finally, the spatial mechanics of freshly harvested LE/wt and LE/orl fetal gubernacula were compared using micropipette aspiration.Results: AR is expressed in the nucleus of mesenchymal core, tip and cord cells of the embryonic (E) day 17 and 21 fetal gubernaculum, and is enhanced by DHT in primary cultures of gubernacular mesenchymal cells. Enhanced AR expression at the tip was observed in LE/wt but not LE/orl gubernacula. In in vitro studies of whole mount fetal gubernaculum, DHT did not alter muscle fiber morphology, HA content or GAG production. Progressive swelling with reduced cellular density of the LE/wt gubernaculum at E19–21 was associated with increased central stiffness in LE/wt but not in LE/orl fetuses.Conclusions: These data confirm nuclear AR expression in gubernacular mesenchyme with distal enhancement at the tip/cord region in LE/wt but not LE/orl rat fetuses. DHT enhanced cellular AR expression but had no major effects on muscle morphology or matrix composition in the rat fetal gubernaculum in vitro. Regional increased stiffness and decreased cell density between E19 and E21 were observed in LE/wt but not LE/orl fetal gubernacula. Developmental differences in cell-specific AR expression in LE/orl fetal gubernacula may contribute to the dysmorphism and aberrant function that underlies cryptorchidism susceptibility in this strain.

Influence of various intensities of 528Hz sound-wave in production of testosterone in rat's brain and analysis of behavioral changes.

Testosterone is a nuclear androgen receptor ligand that controls multiple pathways in brain. In addition to the active biosynthesis of steroids in classic steroidogenic organs such as gonads, adrenals and placenta, testosterone also produced in astrocyte cells of brain. Testosterone and its level must be regulated in brain; because, it directly and indirectly affects memory and several key behavioral characteristics. The significance of sound waves on key enzymes that regulate levels of testosterone in brain has not been investigated. The aim of our study was to examine physical stress of such as sound on induction behavioral changes in animal models. According to the current study, sound waves with 528Hz frequency in 100dB intensity induce testosterone production in brain by enhancing StAR and SF-1 and reducing P450 aromatase gene expression. Frequency of 528Hz also reduces total concentration of reactive oxidative species in brain tissue. Prolonged exposure to this sound wave showed reduction of anxiety related behaviors in rats. The results reveal that reduced anxiety is related to increased concentration of testosterone in brain. This study may lead to ascertain a possible therapy in which sounds may be utilized to reduce anxiety in individual.

Zinc mediates the action of androgen in acting as a downstream effector of luteinizing hormone on oocyte maturation in zebrafish†.

The role of androgenic steroids on ovarian development has attracted much attention in recent years, but the molecular mechanism is still largely unknown. In this study, using zebrafish as a model, we found that the trace metal zinc mediates the action of androgen on oocyte maturation. The ovarian and serum testosterone is transiently stimulated by LH during oocyte maturation. Testosterone could mimic the action of LH on oocyte maturation, and its action appears to be independent of the classical nuclear androgen receptor. Consistent with a recent finding that a zinc transporter (Zip9) has been suggested as a novel androgen receptor, we found the labile zinc concentration could be induced by testosterone in the ovarian follicular cells, and zinc could mimic the action of testosterone on oocyte maturation and signaling. Moreover, the action of testosterone on oocyte maturation could be abolished by the chelation of zinc. Thus, the evidence supports the notion that zinc could mediate the action of androgen on oocyte maturation in zebrafish. This finding would shed light on understanding the role of androgen in ovary development and the molecular mechanism of oocyte maturation in fish.

TGF-β receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer.

Prostate cancer progression is navigated by the androgen receptor (AR) and transforming-growth factor-β (TGF-β) signaling. We previously demonstrated that aberrant TGF-β signaling accelerates prostate tumor progression in a transgenic mouse model of prostate cancer via effects on epithelial-mesenchymal transition (EMT), driving castration-resistant prostate cancer (CRPC). This study examined the antitumor effect of the combination of TGF-β receptor I (TβRI) inhibitor, galunisertib, and FDA-approved antiandrogen enzalutamide, in our pre-clinical model. Age-matched genotypically characterized DNTGFβRII male mice were treated with either galunisertib and enzalutamide, in combination or as single agents in three "mini"-trials and the effects on tumor growth, phenotypic EMT, and actin cytoskeleton were evaluated. Galunisertib in combination with enzalutamide significantly suppressed prostate tumor growth, by increasing apoptosis and decreasing cell proliferation of tumor cell populations compared to the inhibitor as a monotherapy (P < 0.05). The combination treatment dramatically reduced cofilin levels, actin cytoskeleton regulator, compared to single agents. Treatment with galunisertib targeted nuclear Smad4 protein (intracellular TGF-β effector), but had no effect on nuclear AR. Consequential to TGF-β inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-β1 ligand, in response to galunisertib, was blocked by enzalutamide. Our results provide novel insights into the therapeutic value of targeting TGF-β signaling to overcome resistance to enzalutamide in prostate cancer by phenotypic reprogramming of EMT towards tumor re-differentiation and cytoskeleton remodeling. This translational work is significant in sequencing TGF-β blockade and antiandrogens to optimize therapeutic response in CRPC.

Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models.

Following androgen deprivation for the treatment of advanced adenocarcinoma of the prostate, tumors can progress to neuroendocrine prostate cancer (NEPC). This transdifferentiation process is poorly understood, but trafficking of transcriptional factors and/or cytoskeletal rearrangements may be involved. We observed the role of geranylgeranylation in this process by treatment with digeranyl bisphosphonate (DGBP), a selective inhibitor of geranylgeranyl pyrophosphate synthase which blocks the prenylation of small GTPases such as Rho and Rab family proteins, including Cdc42 and Rac1. We examined the therapeutic potential of DGBP in LNCaP, C4-2B4, and 22Rv1 cell culture models. Cell morphology and protein expression were quantified to observe the development of the neuroendocrine phenotype in androgen-deprivation and abiraterone-treated LNCaP models of NEPC development. Luciferase reporter assays were utilized to examine AR activity, and immunofluorescence visualized the localization of AR within the cell. Essential genes in the isoprenoid pathway, such as HMGCR, MVK, GGPS1, and GGT1, were highly expressed in a subset of castration resistant prostate cancers reported by Beltran et al. Under treatment with DGBP, nuclear localization of AR decreased in LNCaP, 22Rv1, and C4-2B4 cell lines, luciferase reporter activity was reduced in LNCaP and 22Rv1, and AR target gene transcription also decreased in LNCaP. Conversely, nuclear localization of AR was enhanced by the addition of GGOH. Finally, induction of the NEPC structural and molecular phenotype via androgen deprivation in LNCaP cells was inhibited by DGBP in a GGOH-dependent manner. DGBP is a novel compound with the potential to reduce AR transcriptional activity and inhibit PCa progression to NEPC phenotype. These results suggest that DGBP may be used to block cell growth and metastasis in both hormone therapy sensitive and resistant paradigms.

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor.

Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.

Intrafollicular level of steroid hormones and the expression of androgen receptor in the equine ovary at puberty

Steroidogenic activity in the equine ovary from birth to puberty has been poorly investigated. This study aimed to examine the capability of the ovarian follicles of prepubertal and pubertal fillies to produce steroid hormones and to evaluate the expression and cellular localization of androgen receptor (AR) in their ovaries. The ovaries of 6–18 month-old fillies were divided into two groups: prepubertal (PrP) – without preovulatory follicle (pF) and corpus luteum (CL), and ovulating/postpubertal (Ov/pB) – with pF and/or CL in at least one of the gonads. Adult mares (Me) were used as a control. The concentration of progesterone (P4), testosterone (T) and estradiol (E2) in follicular fluid (FF) was measured by radioimmunoassay. AR distribution was assessed by immunohistochemistry, while AR protein expression was examined by Western blot analysis. In the female groups, E2 concentration in FF of small follicles (<10 mm) was low and increased with the diameter of the follicle reaching the greatest value in pF (Ov/pB and Me group). In follicles (11–30 mm) of PrP fillies, the concentration of E2 was similar to that from Ov/pB fillies, but less than half (P < 0.05) than in Me follicles. In FF from all classes of follicles of Ov/pB fillies, the concentration of all steroids was similar to that in Me. AR immunolocalization, predominantly nuclear, was observed in all types of follicular cells (granulosa and theca cells) as well as in stroma and luteal cells. The pattern of staining was dependent on the follicle size and the group of females. In smaller antral follicles and in pF, the nuclear AR staining in granulosa cells was stronger than that found in follicles of 21–25 mm. In theca interna cells of pF, both nuclear and faint cytoplasmic reactions were seen. In luteal cells, AR labeling was noted in the nuclei and the cytoplasm: the strongest one in the early CL and almost negative in the late CL. AR protein expression in filly and mare ovarian tissues was confirmed by Western blot analysis and detected as a single band at approximately 110 kDa. In summary, the ovaries of fillies aged at least 6 months are capable of active steroidogenesis. ARs are present either in the cell nuclei or cytoplasm of all compartments of the equine ovary. AR expression in follicular and stroma cells may indicate the sensitivity of the filly ovarian tissue to androgens, the impact of androgens on folliculogenesis and the development of the equine ovary via a receptor-mediated pathway.

Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27)

The androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects in the nucleus by orchestrating the expression of the androgen-regulated transcriptome, there is considerable evidence supporting a rapid, nongenomic activity mediated by membrane-associated AR. Although the genomic action of AR has been studied in depth, the molecular events governing AR transport to the plasma membrane and the downstream AR signaling cascades remain poorly understood. In this study, we report that AR membrane transport is microtubule-dependent. Disruption of the function of kinesin 5B (KIF5B), but not of kinesin C3 (KIFC3), interfered with AR membrane association and signaling. Co-immunoprecipitation and pulldown assays revealed that AR physically interacts with KIF5B and that androgen enhances this interaction. Furthermore, we show that heat shock protein 27 (HSP27) is activated by membrane-associated AR and that HSP27 plays an important role in mediating AR-mediated membrane-to-nuclear signal transduction. Together, these results indicate that AR membrane translocation is mediated by the microtubule cytoskeleton and the motor protein KIF5B. By activating HSP27, membrane-associated AR potentiates the transcriptional activity of nuclear AR. We conclude that disruption of AR membrane translocation may represent a potential strategy for targeting AR signaling therapeutically in prostate cancer.

Abstract 3740: Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling in prostate cancer

Abstract Liver Receptor Homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that is over-expressed in cancers in tissues such as the breast, colon and pancreas. In prostate cancer, LRH-1 is reported as a potent transcription factor to facilitate the formation of CRPC (castration-resistant prostate cancer cells) which is resistant to androgen deprivation therapy (ADT). However, it is still elusive how LRH-1 responses to ADT and facilitates the growth of CRPC. After deprivation of androgen in mouse prostate cancer xenograft model, LRH-1 mRNA was upregulated dramatically at a very low androgen level. After CRPC formation, LRH-1 mRNA was downregulated when androgen level recovered. KLK3/PSA is an important downstream target of activated AR (Androgen receptor), whose expression level at 4 days after castration is downregulated, while upregulated after relapse. Since PSA level/AR signaling activity showed an opposite expression pattern to LRH-1, we hypothesized that LRH-1 was suppressed by androgen in a negative-feedback manner. With androgen treatment of an androgen-sensitive prostate cancer cell line LNCaP, LRH-1 was downregulated in both dose- and time-dependent manner, while PSA shows an opposite expression pattern. And knocking down of AR blocked the suppression of androgen on LRH-1, indicating that androgen suppresses LRH-1 through AR. Furthermore, AR antagonist Enzalutamide can block the binding of androgen to AR thus upregulate LRH-1. According to ChIP-seq data, AR binds to the promoter and enhancer of LRH-1,and the binding intensity increased with androgen treatment. Through ChIP-qPCR, several binding sites of AR on LRH-1 promoter and enhancer were validated. The transcription activity of luciferase reporter with these AR binding sites was also suppressed by treatment of androgen. In the future work, to find out the epigenetics modifiers in the AR complexes when suppressing LRH-1 will be critical for the understanding of the detailed mechanism. Citation Format: Wenxing You, Yuliang Wang, Leung Chan. Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling 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 3740.

Characterization of novel cell lines derived from a MYC-driven murine model of lethal metastatic adenocarcinoma of the prostate.

Loss or mutation of PTEN alleles at 10q23 in combination with 8q24 amplification (encompassing MYC) are common findings in aggressive, human prostate cancer. Our group recently developed a transgenic murine model of prostate cancer involving prostate-specific Pten deletion and forced expression of MYC under the control of the Hoxb13 promoter. MYC overexpression cooperated with Pten loss to recapitulate lethal, human prostate cancer. We now report on the generation of two mouse prostate cancer cell lines, BMPC1 and BMPC2, derived from a lymph node, and liver metastasis, respectively. Both cell lines demonstrate a phenotype consistent with adenocarcinoma and grew under standard tissue culture conditions. Androgen receptor (AR) protein expression is minimal (BMPC1) or absent (BMPC2) consistent with AR loss observed in the BMPC mouse model of invasive adenocarcinoma. Growth in media containing charcoal-stripped serum resulted in an increase in AR mRNA in BMPC1 cells with no effect on protein expression, unless androgens were added, in which case AR protein was stabilized, and showed nuclear localization. AR expression in BMPC2 cells was not effected by growth media or treatment with androgens. Treatment with an anti-androgen/castration or androgen supplemented media did not affect in vitro or in vivo growth of either cell line, irrespective of nuclear AR detection. These cell lines are a novel model of androgen-insensitive prostatic adenocarcinoma driven by MYC over-expression and Pten loss.

Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross-talk in hepatocellular carcinoma.

Nuclear AR overexpression is associated with the progression and prognosis of HCC. However, enzalutamide alone has limited therapeutic utility attributed to feedback activation of the AKT-mTOR pathway. Moreover, mTOR drives nuclear AR overexpression. Cotargeting AR and mTOR is a promising therapeutic strategy for HCC. (Hepatology 2018;67:2271-2286).

Regulation of masculinization: androgen signalling for external genitalia development.

The biology of masculinization is fundamentally important for understanding the embryonic developmental processes that are involved in the development of the male reproductive tract, external genitalia, and also the tumorigenesis of prostate cancer. The molecular mechanisms of masculinization are of interest to many researchers and clinicians involved in varied fields, including molecular developmental biology, cancer research, endocrinology, and urology. Androgen signalling is mediated by the nuclear androgen receptor, which has fundamental roles in masculinization during development. Various modes of androgen signalling, including 5α-dihydrotestosterone-induced regulation of mesenchymal cell proliferation, have been observed in masculinization. Such regulation is essential for regulating urogenital tissue development, including external genitalia development. Androgen-induced genes, such as MAFB, which belongs to the activator protein 1 (AP-1) superfamily of genes, have essential roles in male urethral formation, and disruption of its signalling can interfere with urethral formation, which often results in hypospadias. Another AP-1 superfamily gene, ATF3, could be responsible for some instances of hypospadias in humans. These androgen-dependent signals and downstream events are crucial for not only developmental processes but also processes of diseases such as hypospadias and prostate cancer.

Overcoming resistance to antiandrogens with a TGF-β RI inhibitor in preclinical mouse model of PCa.

288 Background: Epithelial-mesenchymal transition (EMT) is a significant contributor to PCa metastatic progression and therapeutic resistance in patients treated with the androgen receptor (AR) directed therapies. We previously demonstrated that aberrant TGF-β signaling accelerates prostate tumor progression in the TRAMP mouse model of tumorigenesis via selective effects on EMT. Methods: We hypothesize that the combination of the TGF-β receptor inhibitor, galunisertib (G), and enzalutamide (E) will perturb the interactive signaling between TGF-β and AR signaling affecting the phenotypic landscape of EMT. This perturbation may be exploited in our mouse model, towards enhanced anti-tumor efficacy in advanced castration-resistant PCa (CRPC). We treated 2-week old mice for two weeks with the G (75mg/kg) and/or E (30mg/kg) in combination and as single agents. Results: Treatment with G alone or in combination with E resulted in a significant reduction in prostate tumor weight without affecting total body weight. Immunohistochemical (IHC) and Western blot analysis showed that, while treatment with the G alone led to increased apoptosis and decreased cell proliferation, combination of G and E had significantly higher efficacy in inducing apoptosis and inhibiting cell proliferation than either E or G alone. As expected treatment with the G decreased the levels of nuclear Smad4 protein; the combination of G and E further decreased nuclear Smad4 expression. Furthermore the combination of G and E reversed phenotypic EMT to MET (mesenchymal-epithelial-transition), as assessed by the increase in E-cadherin among the prostate tumor cell populations. IHC and Western blot analysis also revealed that the combined treatment of G and E led to a significant decrease in nuclear AR levels compared to E-only-treated or vehicle-control tumors. Conclusions: These results provide significant insights as to the therapeutic impact of G to effectively impair the TGF-β signaling and overcome resistance of PCa patients to E by reversing EMT to potentially sensitize tumors to the antiandrogen effect. This study has major translational relevance; the combination of G and E may lead to synergistic anti-tumor impact in patients with CRPC.

Bone and calcium metabolism associated with malignancy. The function of sex hormone receptors in sex hormone-dependent cancers.

Both Breast and prostate cancers are dependent on the actions of sex hormones mediated through their nuclear receptors in onset and development of the cancers. Nuclear estrogen and androgen receptors(ER and AR)are DNA-binding transcription factors and regulate expressions of the target mRNA genes by modulating chromatin structure and function. In this short review, the function of nuclear sex hormone receptors in sex hormone-depend cancers are overviewed in the chromatin reorganization for target gene regulations. Moreover, the role of enhancer RNA(eRNA), one of the non-coding RNAs, in chromatin reconfiguration is discussed for enhancer function in tumor development.

Nuclear Androgen Receptor Regulates Testes Organization and Oocyte Maturation in Zebrafish

Androgens act through the nuclear androgen receptor (AR) to regulate gonad differentiation and development. In mice, AR is necessary for spermatogenesis, testis development, and formation of external genitalia in males and oocyte maturation in females. However, the extent to which these phenotypes are conserved in nonmammalian vertebrates is not well understood. Here, we generate zebrafish with a mutation in the ar gene (aruab105/105) and examine the role of AR in sexual determination and gonad development. We found that zebrafish AR regulates male sexual determination, because the majority of aruab105/105 mutant embryos developed ovaries and displayed female secondary sexual characteristics. The small percentage of mutants that developed testes displayed female secondary sexual characteristics, exhibited structurally disorganized testes, and were unable to release or produce normal levels of sperm, demonstrating that AR is necessary for zebrafish testis development and fertility. In females, we found that AR regulates oocyte maturation and fecundity. The aruab105/105 mutant females developed ovaries filled primarily with immature stage I oocytes and few mature stage III oocytes. Two genes whose expression is enriched in wild-type ovaries compared with testes (cyp19a1a, foxl2a) were upregulated in ar mutant testes, and two genes enriched in testes (amh, dmrt1) were upregulated in ar mutant ovaries. These findings demonstrate that AR regulates sexual determination, testis development, and oocyte maturation and suggest that AR regulates sexually dimorphic gene expression. The ar mutant we developed will be useful for modeling human endocrine function in zebrafish.

Neuroanatomical and molecular correlates of cognitive and behavioural outcomes in hypogonadal males.

Robust epidemiological, clinical and laboratory evidence supports emerging roles for the sex steroids in such domains as neurodevelopment, behaviour, learning and cognition. Regions of the mammalian brain that are involved in cognitive development and memory do not only express the classical nuclear androgen receptor, but also the non-genomic membrane receptor, which is a G protein-coupled receptor that mediates some rapid effects of the androgens on neurogenesis and synaptic plasticity. Under physiological conditions, hippocampal neurons do express the enzyme aromatase, and therefore actively aromatize testosterone to oestradiol. Although glial expression of the aromatase enzyme is minimal, increased expression following injury suggests a role for sex steroids in neuroprotection. It is therefore plausible to deduce that low levels of circulating androgens in males would perturb neuronal functions in relation to cognition and memory, as well as neural repair following injury. The present review is an overview of some roles of the sex steroids on cognitive function in males, and the neuroanatomical and molecular underpinnings of some behavioural and cognitive deficits characteristic of such genetic disorders noted for low androgen levels, including Klinefelter syndrome, Bardet-Biedl syndrome, Kallman syndrome and Prader-Willi syndrome. Recent literature in relation to some behavioural and cognitive changes secondary to surgical and pharmacological castration are also appraised.

Androgen Receptor in Stage I-II Primary Breast Cancer -Prognostic Value and Distribution in Subgroups.

The value of androgen receptor (AR) in breast cancer has gained renewed interest as a prognostic and treatment predictive biomarker. The aims of this work were to study the associations and the prognostic value of AR in patients from two clinical cohorts. Cohort 1 included 208 premenopausal, node-negative patients of whom 87% had received no adjuvant medical treatment; cohort 2 consisted of 263 patients with stage II disease who had all received 2 years of adjuvant tamoxifen. A semi-quantitative assessment of nuclear AR expression divided into five groups (0-1%, 2-10%, 11-50%, 51-75%, and 76-100%) was performed. Survival analyses, stratified by cohort, were performed using both a trend-test and a cut-off of >10% for positivity. A total of 76% of all patients were AR+, and 89%, 48%, and 23% of the estrogen receptor-positive, negative, and triple-negative, respectively. In Cox regression, stratified by cohort, AR divided into five groups was a prognostic factor for 5-year distant disease-free survival with a hazard ratio of 0.86 per step in fraction score (p=0.018). With a predefined cut-off at 10%, moderate evidence of an effect remained (Hazard Ratio=0.67, p=0.077). In multivariable analysis, AR did not retain an independent prognostic value. AR is a weak, however, not independent prognostic factor for distant metastasis. Although the prognostic value of AR may be questionable, the study identified a subset of AR-positive triple-negative patients as being potential candidates for AR-directed therapy for which further studies are warranted.