Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Androgen Receptor Promotes Lung Cancer Metastasis by Modifying the miR23a-3p/EPHB2 Pathway

Objective This study aimed to investigate the reasons behind the lower survival rates in male lung cancer patients than in female lung cancer patients.Methods Through various techniques,such as Argonaute immunoprecipitation,luciferase assays,and ChIP,this study confirmed the positive effects of androgen receptor(AR)on lung cancer cell invasion across different in vitro cell lines and in vivo mouse models.Results The findings suggest that AR enhanced the invasion of lung cancer cells by modifying EPHB2 signals at the protein expression level,which in turn required changes in miRNA-23a-3p.Restoring miRNA-23a-3p could counteract the intensified invasion of lung cancer cells mediated by AR.Conclusion This study revealed that AR may facilitate the lung cancer matastasis by modulating miRNA-23a-3p/EPHB2 signaling and that targeting this signaling pathway could provide new approaches to inhibit lung cancer metastasis.

三阴性乳腺癌组织中EGR1、AR、H3K4me3表达与其临床病理特征及预后的相关性

目的探讨三阴性乳腺癌组织中早期生长反应基因1(EGR1)、雄激素受体(AR)、组蛋白H3第4位赖氨酸三甲基化(H3K4me3)表达与其临床病理特征及预后的相关性。方法回顾性分析89例三阴性乳腺癌患者的临床资料,所有患者均行手术治疗,采用免疫组化染色法测定EGR1、AR、H3K4me3表达,比较肿瘤组织及癌旁正常组织内EGR1、AR、H3K4me3表达差异,分析EGR1、AR、H3K4me3表达与其临床病理的关系,分析EGR1、AR、H3K4me3表达与其预后的关系。结果肿瘤组织内EGR1阳性表达率、AR阳性表达率低于对照组,H3K4me3阳性表达率高于对照组,差异有统计学意义(P<0.05);EGR1阳性表达、AR阳性表达患者临床分期Ⅰ~Ⅱ期、无淋巴结转移、中高分化占比高于EGR1阴性表达、AR阴性表达患者,H3K4me3阳性表达患者临床分期Ⅲ期、淋巴结转移、低分化占比高于H3K4me3阴性表达患者,差异有统计学意义(P<0.05);随访1年,89例患者共36例出现复发转移,发生率为40.45%(36/89);复发转移组EGR1阳性表达、AR阳性表达率低于未复发转移组,H3K4me3阳性表达率高于未复发转移组,差异有统计学意义(P<0.05)。结论EGR1、AR在三阴性乳腺癌中多呈阴性表达,H3K4me3则以阳性表达为主,三者表达均与临床分期、淋巴结转移及分化程度存在密切关系,或可作为临床治疗的新靶点。

AR、SKP2、SOX10、PD-L1及TIL表达在三阴性乳腺癌中的意义

目的:探索雄激素受体(androgen receptor,AR)、S期激酶相关蛋白2(S-phase kinase-associated protein 2,SKP2)、性别决定区Y相关的HMG盒含因子10(sry-related HMG box-containing factor 10,SOX10)、程序性死亡配体1(programmed death-ligand 1,PD-L1)及肿瘤浸润性淋巴细胞(tumor infiltrating lymphocyte,TIL)在三阴性乳腺癌(triple negative breast cancer,TNBC)表达与临床病理特征和预后的关系。方法:根据苏木精-伊红染色(hematoxylineosin, HE)染色切片评判109例TNBC瘤巢内TIL的比例,采用Leica Bond-Max全自动免疫组化仪检测TNBC组织中AR、SKP2、SOX10、PD-L1的表达。分析以上各生物指标与临床病理特征间的关系,并采用kaplan-Meier、Log-rank进行生存分析。结果:95例患者获得随访,中位随访时间为48个月,中位无病生存时间(disease-free survival, DFS)为42个月,中位总生存时间(overall survival, OS)48个月。在TNBC中,AR阳性表达与淋巴结转移阴性(P=0.009)、肿瘤最大径<2 cm(P=0.008)相关,TIL高表达与低级别TNBC相关(P=0.007),SKP2阳性表达与神经/脉管侵犯阳性(P=0.011)、高级别TNBC相关(P=0.002),SOX10阳性表达与淋巴结转移阳性(P=0.022)、高级别TNBC(P=0.005)相关,PD-L1阳性表达与淋巴结转移阳性(P=0.020)、神经/脉管侵犯阳性(P=0.006)、高级别TNBC(P=0.042)相关。生存分析显示,SKP2、SOX10阳性表达与更差的DFS(P=0.007、P<0.001)和OS(P=0.013、P<0.001)相关,TIL高表达与更好的DFS(P=0.016)及OS(P=0.004)相关。在生物表志物的联合表达中,AR+/SKP2-、AR+/SOX10-与更好的DFS(P=0.004、P<0.001)及OS(P=0.007、P=0.001)相关,SOX10+/低TIL、PD-L1+/低TIL与更差的DFS(P<0.001、P=0.008)及OS(P=0.001、P=0.002)相关,AR-/低TIL者具有更差的OS(P=0.014)。SKP2(HR=4.143,95%CI为1.578~10.875)、SOX10(HR=7.578,95%CI为2.067~27.782)的阳性表达是影响TNBC患者DFS的独立预后因子,SKP2(HR=3.758,95%CI为1.400~10.084)、SOX10(HR=5.131,95%CI为1.316~20.000)及TIL(HR=0.375,95%CI为0.154~0.917)的阳性表达是TNBC患者OS的独立预后因子(P均<0.05)。结论:在TNBC中,AR阳性、TIL高表达与具有更好预后的临床病理特征相关,SKP2、SOX10和PD-L1与具侵袭性的临床病理特征相关。SKP2、SOX10及TIL表达与TNBC预后相关,提示这些生物指标可能成为TNBC新的预后因子,同时它们也有可能成为潜在的治疗靶点。

乳腺癌ER、AR表达与术前MRI征象的相关性分析

目的探讨乳腺癌ER、AR表达与术前MRI征象的相关性。方法收集甘肃省妇幼保健院2019年1月至2022年1月乳腺癌患者共计234例,依据术后免疫组化将其分为ER、AR双表达组、共计155例,ER、AR非双表达组、共计79例,采用Sperman及两独立样本t检验对ER、AR双表达与术前MRI征象进行单因素相关性分析,筛选存在统计学意义的MRI征象并进行多因素Logistic相关性分析。结果乳腺癌AR、ER表达与肿瘤形态之间差异无统计学意义(均P>0.05),与瘤体直径、环形强化及瘤周水肿之间差异具有统计学意义(均P<0.05),乳腺癌AR、ER双表达者肿瘤直径更小,环形强化及瘤周水肿更少见,二元Logistic回归分析表明环形强化(OR=0.421,P=0.041),瘤周水肿(OR=0.505,P=0.025)与乳腺癌AR、ER双表达相关。结论术前MRI征象与乳腺癌AR、ER双表达有较好的相关性,乳腺癌AR、ER双表达者瘤周水肿、环形强化少见,肿瘤组织学分级低,侵袭性弱。

Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers

Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class&#x02005;I&#x02005;chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these &#x0201c;difficult to treat&#x0201d; cancers.

In situ hybridization assay of androgen receptor gene in hepatocarcinogenesis

AIM To determine the correlation between expression of androgen receptor (AR) gene and hepatocarcinogenesis. METHODS Male SD rats were used as experimental animals and the animal model of experimental hepatocarcinoma was established by means of 3′ me DAB administration. Androgen receptor mRNA was detected by a non radioactive in situ hybridization assay in neoplastic and non neoplastic liver tissues. RESULTS The expression of androgen receptor mRNA was observed only in neoplastic cells and some atypical hyperplastic cells. In the liver tissue of control animal and the remaining normal liver cells adjacent to the carcinoma tissue, no positive signal was seen. CONCLUSION Androgen has an important correlation with hepatocarcinogenesis and the expression of androgen receptor gene might be a mark event during hepatocarcinogenesis.

Androgen receptors are expressed in a variety of human fetal extragenital tissues： an immunohistochemical study

Aim： To investigate the expression of androgen receptors in the extragenital tissues of developing human embryo. Methods： Using immunohistochemistry, we investigated the distribution of androgen receptor （AR） in the extragenital tissues of paraffin-embedded tissue sections of first trimester （8-12 weeks gestation） human embryos. Gender was determined by polymerized chain reaction. Results： There were no differences in the expression and distribution of AR in male and female embryos at any stage of gestation. AR expression was seen in the thymus gland. The bronchial epithelium of the lungs showed intense positive staining with surrounding stroma negative. Furthermore, positive staining for androgen receptor was exhibited in the spinal cord with a few positive cells in the surrounding tissues. Cardiac valves also showed strong positive staining but with faint reactivity of the surrounding cardiac muscle. There was no staining in kidney, adrenal, liver or bowel. Conclusion： This study demonstrates that immunoreactive AR protein is present in a wide variety of human first trimester fetal tissues and shows the potential for androgen affecting tissues, which are mostly not considered to be androgen dependent. Moreover, it implies that androgen might act as atrophic factor and affect the early development of these organs rather than simply sexual differentiation.

Localization and potential function of androgen receptor in rat salivary gland

Aim： To investigate the localization and quantity of androgen receptor （AR） in the salivary glands of rats with further analysis on the effect of castration. Methods： Sixty male Wistar rats, aged 30-60 days, were randomly divided into three groups （castrated, sham-operated and normal controls） with 20 rats in each group. The rats in the castrated group were castrated and the submaxillary glands were removed after 1 week. The salivary glands of the rats in the sham-operated and the normal control groups were also removed. Parts of the salivary glands were fixed for immuohistochemistry and in situ hybridization assays. Other parts were used for Western blot. Results： AR immunoreactivity in the three groups was localized in the glandular epithelial cells of the serous acinus and the glandular duct of the salivary gland, mainly in the nuclei. AR mRNA hybridization signals in the salivary glands of the castrated group were mainly distributed in the epithelial cells of the convoluted and secretary ducts; AR mRNA in the sham-operated and the normal control groups were found in the epithelial cells of the convoluted, the secretary and the excretory ducts. The quantity of AR in the salivary glands was decreased significantly in the castrated rats compared with the sham-operated and the normal controls. Moreover, epidermal growth factor （EGF） secreted by the salivary glands was also decreased in the castrated rats. Conclusion： Castration appears to affect the production of AR in the salivary gland and the distribution of the AR mRNA and could further affect the function of the salivary gland. The changes of AR and the distribution of AR mRNA may play an important role in the interactions between the testes and the salivary gland. （Asian J Androl 2005 Sep; 7： 295-301）

SARMs在肌少症治疗中的机制与进展

肌少症(sarcopenia)是当前一类严重影响老年人的日常行为能力和生活质量的疾病。因其发病率逐年增多,近些年各专家对于肌少症的研究也逐步深入。肌少症的治疗方法和治疗药物的研究备受关注,其中,选择性雄激素受体调节剂(selective androgen receptor modulators,SARMs)是一大研究热点,本篇综述的主要目的是探讨SARMs在肌少症的发生发展中的作用机制、研究和临床进展,以便于未来能更快更好地应用于临床治疗。

Expression of androgen receptor target genes in skeletal muscle

We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor （AR）-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity （AR△ZF2） versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR△ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7, p57Kip2, IEf2 and calcineurin Aa, was increased in AR△ZF2 muscle, and the expression of all but p57kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.

Sex Hormones and Androgen Receptor:Risk Factors of Coronary Heart Disease in Elderly Men

Objective To investigate the variation of sex hormone and its receptor level in elderly male patients with coronary heart disease (CHD) and to evaluate the correlations between CHD and sex hormone as well as sex hormone receptor. Methods Altogether 139 male CHD patients (CHD group) aged 60-92 years and 400 healthy men (control group) aged 60-90 years were included in this cross sectional study. The plasma concentrations of dehydroepiandrosterone sulfate (DHEAS),total testosterone (TT),free testosterone (FT),estradiol (E2),sex hormone binding globulin (SHBG),luteinizing hormone (LH),and follicle-stimulating hormone (FSH) were measured. The androgen receptor (AR) was tested by flow cytometry. Correlations between CHD and levels of sex hormones and AR were analyzed. Results Compared with the control group,the levels of DHEAS,TT,FT,SHBG,and the fluorescence intensity of AR in the CHD group significantly reduced (P<0.05),while the levels of FSH and E2 significantly increased (P<0.01). Age was negatively correlated with TT (r=-0.28,P=0.00) and FT (r=-0.17,P=0.01),while it was positively correlated with SHBG (r=0.14,P=0.04) and E2 (r=0.33,P=0.00). AR fluorescence intensity was negatively correlated with systolic blood pressure (r=-0.12,P=0.01). Binary logistic regression analysis showed that TT,SHBG,and AR were all negatively correlated with CHD (P<0.05). Conclusions Elderly male patients with CHD are found to have low levels of DHEAS,TT,FT,SHBG,and AR,while high concentrations of E2 and FSH. Low levels of TT and SHBG may be the potential risk factors of CHD in elderly men.

Therapeutic targeting of the androgen receptor(AR)and AR variants in prostate cancer

Prostate cancer(PCa)accounted for over 300000 deaths world-wide in 2018.Most of the PCa deaths occurred due to the aggressive castration-resistant PCa(CRPC).Since the androgen receptor(AR)and its ligands contribute to the continued growth of androgendependent PCa(ADPCa)and CRPC,AR has become a well-characterized and pivotal therapeutic-target.Although AR signaling was identified as therapeutic-target in PCa over five-decades ago,there remains several practical issues such as lack of antagonist-bound AR crystal structure,stabilization of the AR in the presence of agonists due to N-terminus and C-terminus interaction,unfavorable large-molecule accommodation of the ligand-binding domain(LBD),and generation of AR splice variants that lack the LBD that impede the discovery of highly potent fail-safe drugs.This review summarizes the AR-signaling pathway targeted therapeutics currently used in PCa and the approaches that could be used in future ARtargeted drug development of potent next-generation molecules.The review also outlines the discovery of molecules that bind to domains other than the LBD and those that inhibit both the full length and splice variant of ARs.

Correlations between Expression of Estrogen and Androgen Receptors and the Clinical Characteristics of Prolactinoma~*

Objective： To study the correlations between estrogen receptor （ER） and androgen receptor （AR） and the clinical presentations of prolactinoma and investigate the effect of ER and AR expression on the pathogenesis of prolactinoma in sexual difference. Methods： The clinical data of 30 patients who had undergone transsphenoidal operations in Tongji Hospital from December 2000 to December 2001 were reviewed retrospectively. The clinical information included sex, age, serum-prolactin, size, tumor invasiveness, history of use of bromocriptine and frequency of recurrence. In 20 out of the 30 patients, the ER and AR expression was detected by using immunohistochemistry method. With help of Chi-square test, the relationship between ER, AR and the clinical presentations was analyzed. Results： The statistical values revealed that there was no significant correlation between the ER and AR expression levels with the clinical presentations such as sex, age, tumor size or tumor invasiveness among the 20 patients studied （P〉0.05）. Conclusion： The expression of ER or AR is not influenced by the clinical data of prolactinoma such as sex, age, tumor diameter or extent of tumor invasiveness. The tumor is more aggressive in males than in females. In maroadenoma or tumor with hyperprolactineamia （〉200 ng/mL） simple surgical treatment can＇t successfully cure the prolactinoma. Post-operative bromocriptine therapy can＇t be determined by the sex of the patients, but is greatly related to the tumor size and serum-prolactin level before operation.

Inhibitory Effects of Cypermethrin on Interactions of the Androgen Receptor with Coactivators ARA70 and ARA55

Objective The purpose of this study was to investigate the anti-androgenic mechanism of cypermethrin involving coactivators.Methods Mammalian two-hybrid assays were performed to study the effects of cypermethrin on interactions of the androgen receptor(AR)with the coactivators androgen receptor-associated protein70(ARA70)and androgen receptor-associated protein 55(ARA55).Results The results showed that AR–ARA70 and AR–ARA55 interactions were remarkably enhanced by dihydrotestosterone(DHT,P≤0.05).Cypermethrin inhibited DHT-induced AR–ARA70 and AR–ARA55 interactions significantly(P≤0.05).Conclusion The study indicates that cypermethrin exhibits inhibitory effects on AR transcription associated with repression of AR–ARA70 and AR–ARA55 interactions in a ligand-dependent manner.The data show novel anti-androgenic mechanisms of cypermethrin that contribute to male reproductive toxicology.

Detection of androgen receptor (AR) and AR-V7 in small cell prostate carcinoma: Diagnostic and therapeutic implications

Objective:Small cell prostate carcinoma(SCPC)is a rare and highly malignant subtype of prostate cancer.SCPC frequently lacks androgen receptor(AR)and prostate-specific antigen(PSA)expression,and often responds poorly to androgen deprivation therapy(ADT).AR splice variant-7(AR-V7)is a truncated AR protein implicated in resistance to AR-targeting therapies.AR-V7 expression in castration-resistant prostate cancers has been evaluated extensively,and blood-based detection of AR-V7 has been associated with lack of response to abiraterone and enzalutamide.However,whether AR-V7 is expressed in SCPC is not known.Methods:Using validated antibodies,we performed immunohistochemistry(IHC)assay for the full-length AR(AR-FL)and(AR-V7)on post-ADT surgical SCPC specimens.Results:Seventy-five percent(9/12)of the specimens showed positive staining for the AR-FL with various intensities.Thirty-three percent(4/12)of the specimens showed positive staining for AR-V7.Among the specimens with positive AR-V7 staining,two samples displayed very weak staining,one sample showed weak-to-moderate staining,and one sample showed strong staining.All positive specimens displayed a heterogeneous pattern of AR-FL/AR-V7 staining.All specimens positive for AR-V7 were also positive for AR-FL.Conclusion:The study findings support the existence of measurable AR-FL and AR-V7 proteins in SCPC specimens.The results also have implications in detection of AR-V7 in specimens obtained through systemic sampling approaches such as circulating tumor cells.A positive AR-V7 finding by blood-based tests is not impossible in patients with SCPC who often demonstrate low PSA values.

Current strategies for targeting the activity of androgen receptor variants

Current therapies for advanced prostate cancer,such as enzalutamide and abiraterone,focus on inhibiting androgen receptor(AR)activity and reducing downstream signaling pathways to inhibit tumor growth.Unfortunately,cancer cells are very adaptable and,over time,these cells develop mechanisms by which they can circumvent therapeutics.One of the many mechanisms that have been discovered is the generation of AR variants.These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain.This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand.The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity.Among these are the antihelminthic drug,niclosamide,which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone.Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains,which are retained in most AR variants.The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials.In this review,we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.

Androgen receptor in bladder cancer:A promising therapeutic target

There has been a significant progress in the treatment of metastatic urothelial carcinoma in the last few years with the advent of immunotherapy after a long gap of no drug approvals for over 4 decades.While immunotherapy with checkpoint inhibitors has revolutionized the treatment of urothelial carcinoma,unfortunately,only a minority of patients respond to immunotherapy.Treatment options for patients who do not respond and/or progress on immunotherapy are very limited and overall prognosis remains dismal in metastatic urothelial carcinoma.The first targeted therapy targeting the fibroblast growth factor receptor(FGFR)was recently approved for bladder cancer,but it is effective only in select patients harboring the FGFR2 and FGFR 3 mutations.Antibody drug conjugates like enfortumab vedotin have shown promising activity in clinical trials.Development of novel targeted therapies remains an area of investigation and an unmet need in bladder cancer.Exploitation of androgen receptor(AR)is a potential strategy for targeted drug development in bladder cancer.A significant proportion of urothelial carcinoma patients express AR irrespective of gender.AR signaling in urothelial carcinoma has been linked to progression through multiple mechanisms,including activation of human epidermal growth factor receptor-2(EGFR or HER-2)signaling and epithelial to mesenchymal transition(EMT).Furthermore,AR is enriched in the luminal papillary mRNA subtype of urothelial carcinoma and also mediates resistance to cisplatin-based chemotherapy.Preclinical evidence suggests that AR inhibition can successfully inhibit urothelial carcinoma growth as monotherapy and is synergistic with cisplatin-based chemotherapy.We review the preclinical and clinical evidence supporting the putative role of AR signaling in urothelial carcinoma pathogenesis,progression and its role as a novel therapeutic target and future directions.

Targeting androgen receptor-independent pathways in therapy-resistant prostate cancer

Since androgen receptor(AR)signaling is critically required for the development of prostate cancer(PCa),targeting AR axis has been the standard treatment of choice for advanced and metastatic PCa.Unfortunately,although the tumor initially responds to the therapy,treatment resistance eventually develops and the disease will progress.It is therefore imperative to identify the mechanisms of therapeutic resistance and novel molecular targets that are independent of AR signaling.Recent advances in pathology,molecular biology,genetics and genomics research have revealed novel AR-independent pathways that contribute to PCa carcinogenesis and progression.They include neuroendocrine differentiation,cell metabolism,DNA damage repair pathways and immune-mediated mechanisms.The development of novel agents targeting the non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies.

Physiological Testosterone Retards Cardiomyocyte Aging in Tfm Mice via Androgen Receptor-independent Pathway

Objective To determine whether testosterone modulates markers of cardiomyocytes aging via its classic androgen receptor （AR）-dependent pathway or conversion to estradiol. Methods Male littermates and testicular feminized （Tfm） mice were randomly separated into 4 experimental groups： littermate controls （n=8）, Tfm mice （n=7）, testosterone-treated Tfm mice （n=8） and Tfm mice treated with testosterone in combination with the aromatase inhibitor anastrazole （n=7）. Cardiomyocytes were isolated from mouse left ventricles, the activity of superoxide dismutase （SOD） and glutathione peroxidase （GSH-Px）, and the amount of malondialdehyde （MDA） were measured us- ing colorimetry method, and expression of p l 6~NKga and retinoblastoma （Rb） proteins were detected by Western blotting. Results The SOD and GSH-Px enzyme activities of cardiomyocytes were decreased, and the MDA levels and the expression of p l 6INK＊a and Rb proteins were increased in Tfm mice compared with control mice. An increase was observed in the activities of SOD and GSH-Px enzyme as well as a decrease in MDA levels and the expression of p 16~NK4a and Rb proteins in the testosterone-treated Tfm mice. After co-treatment with anastrazole in Tfm mice, these improvement were partly inhib- ited. Conclusion Physiological testosterone replacement can delay cardiomyocyte aging in Tfm mice, an effect that is independent of the AR pathway and in part conversion to estradiol.