Gene Summary

Gene:AR; androgen receptor
Summary:The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:androgen receptor
Source:NCBIAccessed: 13 March, 2017


What does this gene/protein do?
Show (71)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Ubiquitin-Protein Ligases
  • Cell Proliferation
  • Prostate
  • Antineoplastic Agents
  • Immunohistochemistry
  • Biomarkers, Tumor
  • AR
  • Ubiquitin-Conjugating Enzymes
  • Multiple Myeloma
  • Prostatic Neoplasms, Castration-Resistant
  • Zinc Finger Protein GLI1
  • Cancer Stem Cells
  • Melanoma
  • Transcription Factors
  • Protein Binding
  • Tosyl Compounds
  • Rhabdomyosarcoma
  • Disease Progression
  • Apoptosis
  • Genetic Predisposition
  • RNA Interference
  • Prostate-Specific Antigen
  • Cell Movement
  • Trans-Activators
  • X Chromosome
  • Phenylthiohydantoin
  • Mutation
  • Androgens
  • Pancreatic Cancer
  • Gene Expression Profiling
  • Repetitive Sequences, Nucleic Acid
  • Androgen Receptors
  • Bladder Cancer
  • Western Blotting
  • Cell Survival
  • Messenger RNA
  • fms-Like Tyrosine Kinase 3
  • Drug Resistance
  • Breast Cancer
  • Cancer Gene Expression Regulation
  • Prostate Cancer
  • MicroRNAs
  • RT-PCR
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AR (cancer-related)

Dondoo TO, Fukumori T, Daizumoto K, et al.
Galectin-3 Is Implicated in Tumor Progression and Resistance to Anti-androgen Drug Through Regulation of Androgen Receptor Signaling in Prostate Cancer.
Anticancer Res. 2017; 37(1):125-134 [PubMed] Related Publications
BACKGROUND: Castration-resistant prostate cancer (CRPC)-related deaths are increasing worldwide. Therefore, clarification of the mechanisms of hormone-related tumor progression and resistance to anti-androgen drugs is useful in order to develop strategies for appropriate treatment of CRPC. Galectin-3 has been shown to be correlated with tumor progression in a variety of cancer types through the regulation of tumor proliferation, angiogenesis, and apoptosis.
MATERIALS AND METHODS: We examined tumor cell invasion and migration using the xCELLigence system. Control LNCaP and galectin-3-expressing LNCaP (LNCaP-Gal-3) cells were cultured with androgen-depleted medium with 5% charcoal-stripped serum. Cells were treated for 24 h with or without dihydrotestosterone alone or combined with MDV3100 and bicalutamide; gene profile was then analyzed by microarray analysis and mRNA expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). We evaluated tumor growth using spheroids and xenograft tumor growth in a mouse model.
RESULTS: In vitro, LNCaP-Gal-3 cells promoted both cell migration and invasion in an androgen-independent manner compared to control LNCaP cells. Galectin-3 also enhanced anchorage-independent growth and xenograft tumor growth even after castration. Importantly, galectin-3 greatly enhanced transcriptional activity of the androgen receptor (AR), especially on treatment with dihydrotestosterone. In microarray and qRT-PCR analyses, galectin-3 increased the expression of several AR-target genes, such as kallikrein-related peptidase 3 (KLK3), and transmembrane protease, serine 2 (TMPRSS2). These AR-target genes were not fully suppressed by anti-androgen drugs such as bicalutamide or MDV3100. Galectin-3 significantly inhibited the effect induced by anti-androgen drugs MDV3100 and bicalutamide, suggesting that galectin-3 may be involved in resistance to anti-androgen drug through enhancement of transcriptional activity of AR and expression of AR-related genes.
CONCLUSION: These results suggest that galectin-3 is a potential target molecule for future treatment of anti-androgen drug-resistant prostate cancer.

Gümus M, Ozgur A, Tutar L, et al.
Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis.
Curr Pharm Biotechnol. 2016; 17(14):1231-1245 [PubMed] Related Publications
BACKGROUND: Despite development of novel cancer drugs, invasive ductal breast carcinoma and its metastasis are still highly morbid. Therefore, new therapeutic approaches are being developed and Hsp90 is an important target for drug design. For this purpose, a series of benzodiazepine derivatives were designed and synthesized as novel Hsp90 inhibitor.
METHODS: Benzodiazepine derivatives anticancer activities were determined by XTT cell proliferation assay against human breast cancer cell line (MCF-7). Effects of the compounds on endothelial function were monitored on human vascular endothelium (HUVEC) cell line as well. In order to determine the anti-proliferative mechanism of the compounds, in silico molecular docking studies were performed between Hsp90 ATPase domain and the benzodiazepine derivatives. Further, these compounds perturbation on Hsp90 ATPase function were tested. Fluorescence binding experiments showed that the derivatives bind Hsp90 effectively. Expression analysis of known cancer drug target genes by PCR array experiments suggest that the benzodiazepine derivatives have remarkable anticancer activity.
RESULTS: A representative Benzodiazepine derivative D5 binds Hsp90 with Kd value of 3,93 μM and with estimated free energy of binding -7.99 (kcal/mol). The compound decreases Hsp90 ATPase function and inhibit Hsp90 client protein folding activity. The compound inhibits expression of both Hsp90 isoforms and key proteins (cell cycle receptors; PLK2 and TERT, kinases; PI3KC3 and PRKCE, and growth factors; IGF1, IGF2, KDR, and PDGFRA) on oncogenic pathways.
CONCLUSION: Benzodiazepine derivatives presented here display anticancer activity. The compounds effect on both breast cancer and endothelial cell lines show their potential as drug templates to inhibit breast cancer and its metastasis.

Shahbazi S, Khorasani M, Mahdian R
Gene expression profile of FVII and AR in primary prostate cancer.
Cancer Biomark. 2016; 17(3):353-358 [PubMed] Related Publications
OBJECTIVES: The ectopic expression of coagulation Factor VII has been shown in various cancers. Recently, F7 gene has been identified as a direct target of the androgen receptor in breast cancer. In this study, we examined the mRNA expression of F7 and AR in clinical sample series of prostate cancer and BPH.
MATERIAL AND METHODS: All the prostate cancer patients were new cases with no medical history of surgery or chemotherapy. The tissue samples were assigned as either prostate cancer tumor (n= 45) harboring at least 80% tumor cell content, or BPH (n= 36). Relative AR and F7 mRNA expression in each tissue sample was normalized to the mean of the Ct values determined for GAPDH and PSA genes.
RESULTS: Mean plasma level of prostate specific antigen (PSA) was 17.82 ± 3.71 ng/ml and 7.71 ± 1.28 ng/ml (Mean ± SEM) in PCa and BPH group, respectively. AR mean expression was up-regulated 22.468 fold in clinical tumor sample cohort (S.E., 0.175-2,916, 95% CI: 0.001-126,764, P= 0.001). The mean expression of F7 gene in tumor tissues relative to PBH samples was 6.981 (S.E., 0.099-413.001, 95% CI: 0.002-34,183, P= 0.012). ANOVA analysis of the gene expression results showed significant correlation between F7 and AR mRNA expression in tumor samples (p< 0.001).
CONCLUSIONS: Our study findings suggest a link between FVII and AR in prostate cancer pathogenesis. F7 gene expression could be up-regulated via various AR mediators affecting the promoter region of the F7 gene. Should this be confirmed by further studies, it may be suggested as a potential contributing factor in prostate cancer.

Mousavian Z, Nowzari-Dalini A, Stam RW, et al.
Network-based expression analysis reveals key genes related to glucocorticoid resistance in infant acute lymphoblastic leukemia.
Cell Oncol (Dordr). 2017; 40(1):33-45 [PubMed] Related Publications
PURPOSE: Despite vast improvements that have been made in the treatment of children with acute lymphoblastic leukemia (ALL), the majority of infant ALL patients (~80 %, < 1 year of age) that carry a chromosomal translocation involving the mixed lineage leukemia (MLL) gene shows a poor response to chemotherapeutic drugs, especially glucocorticoids (GCs), which are essential components of all current treatment regimens. Although addressed in several studies, the mechanism(s) underlying this phenomenon have remained largely unknown. A major drawback of most previous studies is their primary focus on individual genes, thereby neglecting the putative significance of inter-gene correlations. Here, we aimed at studying GC resistance in MLL-rearranged infant ALL patients by inferring an associated module of genes using co-expression network analysis. The implications of newly identified candidate genes with associations to other well-known relevant genes from the same module, or with associations to known transcription factor or microRNA interactions, were substantiated using literature data.
METHODS: A weighted gene co-expression network was constructed to identify gene modules associated with GC resistance in MLL-rearranged infant ALL patients. Significant gene ontology (GO) terms and signaling pathways enriched in relevant modules were used to provide guidance towards which module(s) consisted of promising candidates suitable for further analysis.
RESULTS: Through gene co-expression network analysis a novel set of genes (module) related to GC-resistance was identified. The presence in this module of the S100 and ANXA genes, both well-known biomarkers for GC resistance in MLL-rearranged infant ALL, supports its validity. Subsequent gene set net correlation analyses of the novel module provided further support for its validity by showing that the S100 and ANXA genes act as 'hub' genes with potentially major regulatory roles in GC sensitivity, but having lost this role in the GC resistant phenotype. The detected module implicates new genes as being candidates for further analysis through associations with known GC resistance-related genes.
CONCLUSIONS: From our data we conclude that available systems biology approaches can be employed to detect new candidate genes that may provide further insights into drug resistance of MLL-rearranged infant ALL cases. Such approaches complement conventional gene-wise approaches by taking putative functional interactions between genes into account.

Eiro N, Fernandez-Gomez J, Sacristán R, et al.
Stromal factors involved in human prostate cancer development, progression and castration resistance.
J Cancer Res Clin Oncol. 2017; 143(2):351-359 [PubMed] Related Publications
PURPOSE: To detect new predictive markers from the prostate cancer tissue, to study the expression by cultured cancer-associated fibroblasts (CAFs) of stromal factors implicated in prostate carcinogenesis, and to compare their expressions in localized, metastatic, castration-sensitive (CSCP), castration-resistant prostate tumors (CRCP) as well as in fibroblasts from benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS: The genomic expression of 20 stroma-derived factors, including the androgen receptor (AR), growth factors (FGF2, FGF7, FGF10, HGF, TGFβ, PDGFB), protein implicated in invasion (MMP-2, MMP-9 and MMP-11), inflammation (IL-6, IL-17, STAT-3 and NFκB), stroma/epithelium interaction (CDH11, FAP, CXCL12 and CXCL14) and chaperones (HPA1A and HSF1), was evaluated in cultured fibroblasts both from BHP and prostate carcinomas (PCa). After isolation and culture of fibroblasts by biopsy specimens, RNA was isolated and genomic studies performed.
RESULTS: Finally, 5 BPH and 37 PCa specimens were selected: clinically localized (19), metastatic (5), CSCP (7) and CRPC (6). Interleukin-17 receptor (IL-17RB) was highly expressed in CAFs compared with fibroblasts from BPH. However, metalloproteinase-2 and chemokine ligand 14 (CXCL14) were expressed at higher levels by fibroblasts from BPH. The fibroblastic growth factor-7 was highly expressed by CAFs from localized tumors, but metalloproteinase-11 in metastatic tumors. MMP-11, androgen receptor (AR) and heat-shock-70kda-protein-1A (HSPA1A) expressions were significantly higher in CAFs from CRPC.
CONCLUSIONS: These results demonstrate a CAFs heterogeneity among prostate carcinomas with regard to some molecular profile expressions that may be relevant in tumor development (IL-17RB), progression (MMP-11) and castration resistance (AR, MMP-11 and HSPA1A).

Bubendorf L, Büttner R, Al-Dayel F, et al.
Testing for ROS1 in non-small cell lung cancer: a review with recommendations.
Virchows Arch. 2016; 469(5):489-503 [PubMed] Free Access to Full Article Related Publications
Rearrangements of the ROS1 gene occur in 1-2 % of non-small cell lung cancers (NSCLCs). Crizotinib, a highly effective inhibitor of ROS1 kinase activity, is now FDA-approved for the treatment of patients with advanced ROS1-positive NSCLC. Consequently, focus on ROS1 testing is growing. Most laboratories currently rely on fluorescence in situ hybridisation (FISH) assays using a dual-colour break-apart probe to detect ROS1 rearrangements. Given the rarity of these rearrangements in NSCLC, detection of elevated ROS1 protein levels by immunohistochemistry may provide cost-effective screening prior to confirmatory FISH testing. Non-in situ testing approaches also hold potential as stand-alone methods or complementary tests, including multiplex real-time PCR assays and next-generation sequencing (NGS) platforms which include commercial test kits covering a range of fusion genes. In order to ensure high-quality biomarker testing, appropriate tissue handling, adequate control materials and participation in external quality assessment programmes are essential, irrespective of the testing technique employed. ROS1 testing is often only considered after negative tests for EGFR mutation and ALK gene rearrangement, based on the assumption that these oncogenic driver events tend to be exclusive. However, as the use of ROS1 inhibitors becomes routine, accurate and timely detection of ROS1 gene rearrangements will be critical for the optimal treatment of patients with NSCLC. As NGS techniques are introduced into routine diagnostic practice, ROS1 fusion gene testing will be provided as part of the initial testing package.

Xu J, Lin H, Li G, et al.
The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals.
EBioMedicine. 2016; 12:55-67 [PubMed] Free Access to Full Article Related Publications
The androgen receptor (AR) was found to suppress hepatocellular carcinoma (HCC) metastasis at late stages. Due to this discovery, we searched for some AR enhancers to increase the efficacy of Sorafenib chemotherapy, and identified the microRNA (miR)-367-3p, whose expression is positively correlated with AR expression in advanced HCC, as an HCC metastasis suppressor. Combining miR-367-3p with Sorafenib showed better efficacy to suppress HCC cell invasion in vitro and in vivo. Mechanism dissection revealed that miR-367-3p could increase AR expression via directly targeting the 3'UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FKBP5 and PHLPP, thus dephosphorylating and inactivating AKT and ERK, to suppress the HCC cell invasion. Interestingly, the suppression of pAKT by miR-367-3p could subsequently attenuate the phosphorylation of AR and MDM2, giving rise to additional enhancement of AR protein expression, effectively forming a positive feedback loop. Together, these results suggest that miR-367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FKBP5/PHLPP/(pAKT and pERK) signals to better suppress HCC metastasis. Successful development of this newly combined chemotherapy in the future may help us to better suppress the HCC metastasis at late stages.

Romano RC, Gardner JM, Shalin SC, et al.
High Relative Expression of Pannexin 3 (PANX3) in an Axillary Sweat Gland Carcinoma With Osteosarcomatous Transformation.
Am J Dermatopathol. 2016; 38(11):846-851 [PubMed] Related Publications
Primary cutaneous sweat gland carcinomas (SGCs) are rare tumors that commonly involve axillae, have a high local recurrence rate, and rarely show sarcomatoid transformation. A 68-year-old man presented with rapid enlargement of a previously stable, asymptomatic pea-sized nodule in the left axilla. Initial excision (with positive surgical margins) at another institution showed characteristic histologic features of a high-grade osteosarcoma and molecular analysis using a 92-gene real-time quantitative reverse transcription-polymerase chain reaction assay confirmed a diagnosis of osteosarcoma with 96% certainty. Notably, the molecular assay demonstrated consistently high relative expression of pannexin 3 (PANX3), a gene involved in normal osteoblast differentiation which, when highly expressed, strongly predicts osteosarcoma per the assay's algorithm. However, on further histologic review, the tumor also contained focal cystic areas, nests, and ducts composed of malignant epithelial cells reminiscent of SGC; these areas directly transitioned into the osteosarcomatous component and were strongly positive for pancytokeratin, CK7, and p63. Within 2 weeks, the lesion recurred and grew rapidly, prompting complete resection, histologic sections of which showed high-grade osteosarcoma without residual epithelial elements. This is the fifth report, to our knowledge, of osteosarcomatous transformation in a SGC, and the only report to date including molecular data. This case demonstrates that osteosarcoma arising from a SGC has a similar molecular profile to de novo primary osteosarcoma of bone. It also emphasizes the importance of histopathologic findings as the established diagnostic gold standard and the need to interpret molecular results within the clinical context.

Choi HE, Shin JS, Leem DG, et al.
6-(3,4-Dihydro-1H-isoquinoline-2-yl)-N-(6-methoxypyridine-2-yl) nicotinamide-26 (DIMN-26) decreases cell proliferation by induction of apoptosis and downregulation of androgen receptor signaling in human prostate cancer cells.
Chem Biol Interact. 2016; 260:196-207 [PubMed] Related Publications
Previously, we reported that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl) nicotinamide (DIMN) analogues inhibited the growth of prostate cancer cells as an anti-androgenic compound. In the present study, we evaluated cytotoxic effects of these DIMN derivatives and found that DIMN-26 most potently inhibited the proliferation of the LNCap-LN3 androgen-dependent and DU145 androgen-independent prostate cancer cells through induction of G2/M phase cell cycle arrest and subsequent apoptosis. The G2/M phase arrest was found due to increases in the activation of cdc2 (also known as cyclin-dependent kinase 1, CDK1)/cyclin B1 complex. DIMN-26 also induced apoptosis in LNCap-LN3 and DU145 prostate cancer cells through activation of caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1). In addition, DIMN-26 caused the dephosphorylation and mitochondrial accumulation of Bad protein and induced the loss of mitochondria membrane potential, consequently releasing cytochrome c into the cytosol of the cell. Furthermore, overexpression of AKT protein significantly reduced DIMN-26-induced PARP-1 cleavage and p-Bad decrease and cdc2 activation. In addition, DIMN-26 inhibited the 5α-dihydrotestosterone (DHT)-induced cell growth and proliferation and nuclear translocation and transcriptional activities of androgen receptor (AR) in LNCap-LN3 prostate cancer cells. Consistent with these findings, DIMN-26 significantly inhibited the DHT-induced expression of AR-response genes (ARGs), such as prostate-specific antigen (PSA), AR, β2-microglobulin (B2M), selenoprotein P (SEPP1), and ste20-related proline-alanine-rich kinase (SPAK) in LNCap-LN3 prostate cancer cells. Taken together, these results suggest that DIMN-26 plays a therapeutic role not only in induction of G2/M arrest and apoptosis but also in suppression of androgen receptor signaling in androgen-dependent and androgen-independent prostate cancer cells.

Díaz P, Cardenas H, Orihuela PA
Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.
Andrologia. 2016; 48(8):922-6 [PubMed] Related Publications
We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 μg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 μg/ml of red Maca plus Taxol or 2ME 5 μM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 μg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 μg/ml, but not at 80 μg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells.

Borrie AE, Kim RB
Molecular basis of aromatase inhibitor associated arthralgia: known and potential candidate genes and associated biomarkers.
Expert Opin Drug Metab Toxicol. 2017; 13(2):149-156 [PubMed] Related Publications
INTRODUCTION: Aromatase inhibitors (AIs) are routinely used for the adjuvant treatment of women with hormone receptor-positive early breast cancer. AIs are widely prescribed in the postmenopausal setting, as they are effective at preventing recurrence. However, their use is complicated by significant adverse effects, particularly arthralgia, noted in up to 50% of treated patients, and thereby affects quality of life and AI compliance. The mechanism by which AIs cause arthralgia is largely unknown, although there is a growing body of literature which suggests that there may be multiple intersecting mechanisms. Areas covered: This review describes the evidence for the mechanistic basis of AI arthralgia as well as potential pathways that could contribute to the development of AI associated arthralgia. Expert opinion: Interplay of multiple factors, such as interpatient variability in AI metabolism, possibly related to pharmacogenetic factors, the sudden decline of estrogen synthesis, vitamin D status, as well as upregulation of cytokines and inflammation pathways may precipitate or exacerbate muscle and joint pain are linked during AI therapy. However, much more research is needed in this area given the frequency and severity of AI-associated arthralgia.

Xu H, Cao H, Xiao G
Signaling via PINCH: Functions, binding partners and implications in human diseases.
Gene. 2016; 594(1):10-15 [PubMed] Article available free on PMC after 05/12/2017 Related Publications
Particularly interesting new cysteine-histidine-rich protein (PINCH) is a LIM-domain-only adaptor that plays important roles in cytoskeletal organization and extracellular matrix adhesion, migration, proliferation and survival. Mammalian cells have two functional PINCH proteins, PINCH1 and PINCH2. PINCH not only binds to Nck2 and engages in the signaling of growth factor receptors, but also forms a ternary complex with ILK and parvin (IPP complex). Normally, the IPP complex locates to focal adhesions participating in the signaling of integrins and mediating the interaction of cytoskeleton and extracellular matrix (ECM). Accumulative evidence indicates that abnormalities in PINCH signaling are involved in the pathogenesis of important diseases, such as cancers, renal diseases, cardiomyopathy, and HIV. Therefore, clarifying the functions of PINCH and its interactions with key factors is important for better understanding of signaling events both in health and disease.

Wang W, Liu J, Qi J, et al.
RLIP76 increases apoptosis through Akt/mTOR signaling pathway in gastric cancer.
Oncol Rep. 2016; 36(4):2216-24 [PubMed] Related Publications
RLIP76 is a stress-responsive multifunctional protein and is usually overexpressed in malignant carcinomas. It plays a significant role in multiple cellular biological behaviors, including cell growth, motility, division and apoptosis, in many types of malignant cells. However, functions of RLIP76 in gastric cancer (GC) remain unknown. In the present study, RLIP76 was overexpressed in GC tissues by immunohistochemistry. RLIP76-targeted shRNA-containing lentivirus (KD) and the scrambled shRNA (NC) were used to explore the knockout of RLIP76 on cellular functions of human GC SGC-7901 and MGC-803 cells. Quantitative RT-PCR and western blotting were used to confirm that the RLIP76 was suppressed both on mRNA and protein levels after transfection. The mRNA level in SGC-7901 and MGC-803 after transfection of RLIP76-targeted shRNA was 0.245722±0.021077 (p<0.05) and 0.225389±0.00974 (p<0.05), respectively. Our results showed that the konckdown of RLIP76 downregulated cell growth after 24 h in Cell Counting Kit-8 (CCK-8) assay, reduced migration from 486.7±128.8 to 219.7±43.6 in SGC-7901 (p<0.05) and from 630±95 to 333.7±46.5 in MGC-803 (p<0.05), decreased invasion from 306±33.5 to 97.7±24.3 in SGC-7901 (p<0.05) and from 350±50.9 to 163.3±87.5 in MGC-803 (p<0.05). Length of vascular endothelial growth factor (VEGF)-induced tube formation also decreased from 202.8±83.3 to 44.5±3.69 in SGC-7901 and from 193±3.5 to 71.8±8.83 in MGC-803 (p<0.05). Phosphorylation level of Akt declined from 138.45±13.8 to 69.9±29.7% in SGC-7901, and from 115.5±26.6 to 49.07±27% in MGC-803 (p<0.05) and phosphorylation level of mTOR also significantly decreased (p<0.05). While apoptosis of GC cells increased which we verified with apoptosis proteins and staining analysis. Our data showed that RLIP76 plays a significant oncogenic role in GC and it maybe a potential target in GC treatment.

Caspar A, Mostertz J, Leymann M, et al.
In Vitro Cultivation of Primary Prostate Cancer Cells Alters the Molecular Biomarker Pattern.
In Vivo. 2016 09-10; 30(5):573-9 [PubMed] Related Publications
BACKGROUND/AIM: The high variability of primary cells propagated in vitro led us to study the expression patterns of 11 most commonly accepted and widely used biomarkers specific for prostate cancer (PC) cells in primary cell models.
MATERIALS AND METHODS: Primary PC cells from five PC patients were partially subjected to RNA preparation immediately and remaining cells were propagated up to 84 days followed by RNA preparation. Subsequently, biomarker mRNA quantification was performed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and biomarker transcript concentrations before and after cultivation of primary PC cells were compared.
RESULTS: Evaluation of androgen receptor, prostate-specific antigen, acid phosphatase, prostate-specific membrane antigen, fatty acid synthase, cytokeratin types 5/8/19, E-cadherin, epithelial cell adhesion molecule and fibroblast-specific protein 1 demonstrated temporal changes, as well as individual differences in expression, during primary PC cell propagation.
CONCLUSION: Experimental design, as well as data evaluation, may need to take under consideration the high variability of biomarker expression in primary PC cells.

Colditz J, Rupf B, Maiwald C, Baniahmad A
Androgens induce a distinct response of epithelial-mesenchymal transition factors in human prostate cancer cells.
Mol Cell Biochem. 2016; 421(1-2):139-47 [PubMed] Related Publications
Inhibition of the androgen receptor (AR) is a major target of prostate cancer (PCa) therapy. However, prolonged androgen deprivation results eventually in castration-resistant PCa (CRPC) with metastasis and poor survival. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) may facilitate castration-resistance and cancer metastasis in PCa. The human androgen-dependent, castration-sensitive prostate cancer (CSPC) cell line LNCaP and the CRPC cell line C4-2 are often used as a model system for human PCa. However, the role of the AR and the effect of AR antagonist (antiandrogen) treatment on the RNA expression of key factors of EMT including the long non-coding RNAs (lncRNAs) DRAIC in PCa cells remain elusive. Although as expected the established AR target genes PSA and FKBP5 are strongly induced by androgens in both cell lines, both E-cadherin and vimentin mRNA levels are upregulated by androgens in LNCaP but not in C4-2 cells by short- and long-term treatments. The mRNA levels of E-cadherin and vimentin remain unchanged by antiandrogen treatment in both cell lines. The expression of transcription factors that regulate EMT including Slug, Snail and ZEB1 and the lncRNA DRAIC were affected by androgen treatment in both cell lines. The mRNA level of Slug is upregulated by androgens and interestingly downregulated by antiandrogens in both cell lines. On the other hand, ZEB1 mRNA levels are strongly upregulated by androgens but remain unchanged by antiandrogens. In contrast, Snail mRNA levels are repressed by androgen treatment similar to DRAIC RNA levels. However, while antiandrogen treatment seems not to change Snail mRNA levels, antiandrogen treatments induce DRAIC RNA levels. Moreover, despite the strong upregulation of Zeb1 mRNA, no significant increase of the ZEB1 protein was observed indicating that despite androgen upregulation, posttranscriptional regulation of EMT controlling transcription factors occurs. SLUG protein was enhanced in both cell lines by androgens and reduced by antiandrogens. Taken together, our data suggest that the ligand-activated AR regulates the expression of several EMT key factors and antiandrogens counteract AR activity only on selected genes.

Fialova B, Luzna P, Gursky J, et al.
Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5'-Aza-2'-deoxycytidine.
Oncol Rep. 2016; 36(4):2365-74 [PubMed] Related Publications
The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients.

Sinha AA, Pomroy FE, Wilson MJ
Concurrent Androgen and Estrogen Ablation and Inhibition of Steroid Biosynthetic Enzyme Treatment for Castration-resistant Prostate Cancer.
Anticancer Res. 2016; 36(8):3847-54 [PubMed] Related Publications
BACKGROUND/AIM: About 80 to 90% of prostate cancer (PCa) is androgen-dependent at diagnosis, but patients ultimately develop castration-resistant prostate cancer (CRPC), which is usually not amenable to androgen deprivation (ablation) therapy (ADT). Patients with CRPC usually succumb to death in less than 5 years and there is no cure. Here, we investigated reasons for ADT failure.
MATERIALS AND METHODS: Biopsy specimens from untreated and diethylstilbestrol (DES)-treated patients were assessed for localization of antibody IgGs against androgen (AR) and estrogen (ER) receptors.
RESULTS: In untreated and DES-treated sections, methylene blue stained basic proteins in dark basal (undifferentiated) PCa cells, whereas light basal cells were not stained. AR localized to light basal cells which showed widespread degeneration in sections from DES-treated patients, indicating their dependence on androgen. In contrast, dark basal cells did not show widespread degeneration in DES-treated patients; ER was usually localized in dark cells. The number of dark cells progressively increased in DES-treated patients indicating their androgen-independence. The localization of AR and ER in some light and dark basal cells indicated that the supply of androgen/estrogen was not inhibited during ADT. Dark basal cells had emerged prior to treatment and proliferated during DES treatment, that also indicated their androgen-independence.
CONCLUSION: PCa has at least two populations of cells: androgen-dependent light basal and estrogen-dependent dark basal cells. ADT did not destroy estrogen-dependent cells which may have given rise to CRPC tumors. Therefore, ADT is an incomplete treatment. For a more complete treatment of PCa, we recommend concurrent androgen and estrogen ablation, together with the inhibition of selected steroid biosynthetic enzymes.

Crisp RL, Maltaneri RE, Vittori DC, et al.
Red blood cell aquaporin-1 expression is decreased in hereditary spherocytosis.
Ann Hematol. 2016; 95(10):1595-601 [PubMed] Related Publications
Aquaporin-1 (AQP1) is the membrane water channel responsible for changes in erythrocyte volume in response to the tonicity of the medium. As the aberrant distribution of proteins in hereditary spherocytosis (HS) generates deficiencies of proteins other than those codified by the mutated gene, we postulated that AQP1 expression might be impaired in spherocytes. AQP1 expression was evaluated through flow cytometry in 5 normal controls, 1 autoimmune hemolytic anemia, 10 HS (2 mild, 3 moderate, 2 severe, and 3 splenectomized), and 3 silent carriers. The effect of AQP1 inhibitors was evaluated through water flow-based tests: osmotic fragility and hypertonic cryohemolysis. Serum osmolality was measured in 20 normal controls and 13 HS. The effect of erythropoietin (Epo) on AQP1 expression was determined in cultures of erythroleukemia UT-7 cells, dependent on Epo to survive. Independent of erythrocyte size, HS patients showed a lower content of AQP1 in erythrocyte membranes which correlated with the severity of the disease. Accordingly, red blood cells from HS subjects were less sensitive to cryohemolysis than normal erythrocytes after inhibition of the AQP1 water channel. A lower serum osmolality in HS with respect to normal controls suggests alterations during reticulocyte remodeling. The decreased AQP1 expression could contribute to explain variable degrees of anemia in hereditary spherocytosis. The finding of AQP1 expression induced by Epo in a model of erythroid cells may be interpreted as a mechanism to restore the balance of red cell water fluxes.

Zaretsky JM, Garcia-Diaz A, Shin DS, et al.
Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.
N Engl J Med. 2016; 375(9):819-29 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.
RESULTS: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
CONCLUSIONS: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).

Vega-Benedetti AF, Saucedo C, Zavattari P, et al.
PLAGL1: an important player in diverse pathological processes.
J Appl Genet. 2017; 58(1):71-78 [PubMed] Related Publications
The PLAGL1 gene encodes a homonymous zinc finger protein that promotes cell cycle arrest and apoptosis through multiple pathways. The protein has been implicated in metabolic, genetic, and neoplastic illnesses, but the molecular mechanisms by which the protein PLAGL1 participates in such diverse processes remains to be elucidated. In this review, we focus mainly on the molecular biology of PLAGL1 and the relevance of its abnormalities to several pathological processes.

Liu C, Wu HT, Zhu N, et al.
Steroid receptor RNA activator: Biologic function and role in disease.
Clin Chim Acta. 2016; 459:137-46 [PubMed] Related Publications
Steroid receptor RNA activator (SRA) is a type of long noncoding RNA (lncRNA) which coordinates the functions of various transcription factors, enhances steroid receptor-dependent gene expression, and also serves as a distinct scaffold. The novel, profound and expanded roles of SRA are emerging in critical aspects of coactivation of nuclear receptors (NRs). As a nuclear receptor coactivator, SRA can coactivate androgen receptor (AR), estrogen receptor α (ERα), ERβ, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor and retinoic acid receptor (RAR). Although SRA is one of the least well-understood molecules, increasing studies have revealed that SRA plays a key role in both biological processes, such as myogenesis and steroidogenesis, and pathological changes, including obesity, cardiomyopathy, and tumorigenesis. Furthermore, the SRA-related signaling pathways, such as the mitogen-activated protein kinase (p38 MAPK), Notch and tumor necrosis factor α (TNFα) pathways, play critical roles in the pathogenesis of estrogen-dependent breast cancers. In addition, the most recent data demonstrates that SRA expression may serve as a new prognostic marker in patients with ER-positive breast cancer. Thus, elucidating the molecular mechanisms underlying SRA-mediated functions is important to develop proper novel strategies to target SRA in the diagnosis and treatment of human diseases.

Šemeláková M, Jendželovský R, Fedoročko P
Drug membrane transporters and CYP3A4 are affected by hypericin, hyperforin or aristoforin in colon adenocarcinoma cells.
Biomed Pharmacother. 2016; 81:38-47 [PubMed] Related Publications
Our previous results have shown that the combination of hypericin-mediated photodynamic therapy (HY-PDT) at sub-optimal dose with hyperforin (HP) (compounds of Hypericum sp.), or its stable derivative aristoforin (AR) stimulates generation of reactive oxygen species (ROS) leading to antitumour activity. This enhanced oxidative stress evoked the need for an explanation for HY accumulation in colon cancer cells pretreated with HP or AR. Generally, the therapeutic efficacy of chemotherapeutics is limited by drug resistance related to the overexpression of drug efflux transporters in tumour cells. Therefore, the impact of non-activated hypericin (HY), HY-PDT, HP and AR on cell membrane transporter systems (Multidrug resistance-associated protein 1-MRP1/ABCC1, Multidrug resistance-associated protein 2-MRP2/ABCC2, Breast cancer resistance protein - BCRP/ABCG2, P-glycoprotein-P-gp/ABCC1) and cytochrome P450 3A4 (CYP3A4) was evaluated. The different effects of the three compounds on their expression, protein level and activity was determined under specific PDT light (T0+, T6+) or dark conditions (T0- T6-). We found that HP or AR treatment affected the protein levels of MRP2 and P-gp, whereas HP decreased MRP2 and P-gp expression mostly in the T0+ and T6+ conditions, while AR decreased MRP2 in T0- and T6+. Moreover, HY-PDT treatment induced the expression of MRP1. Our data demonstrate that HP or AR treatment in light or dark PDT conditions had an inhibitory effect on the activity of individual membrane transport proteins and significantly decreased CYP3A4 activity in HT-29 cells. We found that HP or AR significantly affected intracellular accumulation of HY in HT-29 colon adenocarcinoma cells. These results suggest that HY, HP and AR might affect the efficiency of anti-cancer drugs, through interaction with membrane transporters and CYP3A4.

Liu X, Low SK, Boddy AV
The implications of genetic variation for the pharmacokinetics and pharmacodynamics of aromatase inhibitors.
Expert Opin Drug Metab Toxicol. 2016; 12(8):851-63 [PubMed] Related Publications
INTRODUCTION: Breast cancer is the most common female cancer and remains a serious public health concern worldwide. Third-generation aromatase inhibitors (AIs) are widely used in postmenopausal women with estrogen receptor positive breast cancer. However, there is marked interindividual variability in terms of the efficacy and incidence of adverse events following treatment with AIs. Pharmacogenetics has the potential to predict clinical outcomes based on patients' genetic information, paving the way towards personalized treatment.
AREAS COVERED: This article reviews pharmacogenetic studies of AIs, including pharmacokinetic and pharmacodynamic aspects, highlighting those studies where the efficacy and adverse events of AIs have been examined using both candidate gene and genome-wide approaches.
EXPERT OPINION: Pharmacogenetics is a promising approach to develop personalized medicine with AIs. However, the application of pharmacogenetics to predict therapeutic efficacy and adverse events in breast cancer patients is still far from implementation in routine clinical practice. Large, comprehensive, multicenter studies that simultaneously evaluate multiple genes and pathways, including rare variants, are warranted in order to produce reliable and informative results. The ultimate aim is to develop clinically-relevant guidelines for breast cancer therapy.

Beltran H, Antonarakis ES, Morris MJ, Attard G
Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic.
Am Soc Clin Oncol Educ Book. 2016; 35:131-41 [PubMed] Related Publications
Recent clinical and preclinical studies focused on understanding the molecular landscape of castration-resistant prostate cancer (CRPC) have provided insights into mechanisms of treatment resistance, disease heterogeneity, and potential therapeutic targets. This work has served as a framework for several ongoing clinical studies focused on bringing novel observations into the clinic in the form of tissue, liquid, and imaging biomarkers. Resistance in CRPC typically is driven through reactivation of androgen receptor (AR) signaling, which can occur through AR-activating point mutations, amplification, splice variants (such as AR-V7), or other bypass mechanisms. Detection of AR aberrations in the circulation negatively impacts response to subsequent AR-directed therapies such as abiraterone and enzalutamide. Other potentially clinically relevant alterations in CRPC include defects in DNA damage repair (at either the somatic or germline level) in up to 20% of patients (with implications for PARP1 inhibitor therapy), PI3K/PTEN/Akt pathway activation, WNT signaling pathway alterations, cell cycle gene alterations, and less common but potentially targetable alterations involving RAF and FGFR2. Imaging biomarkers that include those focused on incorporating overexpressed androgen-regulated genes/proteins, such as prostate-specific membrane antigen (PSMA) and dihydrotestosterone (DHT) in combination with CT, can noninvasively identify patterns of AR-driven distribution of CRPC tumor cells, monitor early metastatic lesions, and potentially capture heterogeneity of response to AR-directed therapies and other therapeutics. This article focuses on the current state of clinical biomarker development and future directions for how they might be implemented into the clinic in the near term to improve risk stratification and treatment selection for patients.

Yunoki T, Tabuchi Y, Hayashi A, Kondo T
Network analysis of genes involved in the enhancement of hyperthermia sensitivity by the knockdown of BAG3 in human oral squamous cell carcinoma cells.
Int J Mol Med. 2016; 38(1):236-42 [PubMed] Related Publications
BCL2-associated athanogene 3 (BAG3), a co-chaperone of the heat shock 70 kDa protein (HSPA) family of proteins, is a cytoprotective protein that acts against various stresses, including heat stress. The aim of the present study was to identify gene networks involved in the enhancement of hyperthermia (HT) sensitivity by the knockdown (KD) of BAG3 in human oral squamous cell carcinoma (OSCC) cells. Although a marked elevation in the protein expression of BAG3 was detected in human the OSCC HSC-3 cells exposed to HT at 44˚C for 90 min, its expression was almost completely suppressed in the cells transfected with small interfering RNA against BAG3 (siBAG) under normal and HT conditions. The silencing of BAG3 also enhanced the cell death that was increased in the HSC-3 cells by exposure to HT. Global gene expression analysis revealed many genes that were differentially expressed by >2-fold in the cells exposed to HT and transfected with siBAG. Moreover, Ingenuity® pathways analysis demonstrated two unique gene networks, designated as Pro-cell death and Anti-cell death, which were obtained from upregulated genes and were mainly associated with the biological functions of induction and the prevention of cell death, respectively. Of note, the expression levels of genes in the Pro-cell death and Anti-cell death gene networks were significantly elevated and reduced in the HT + BAG3-KD group compared to those in the HT control group, respectively. These results provide further insight into the molecular mechanisms involved in the enhancement of HT sensitivity by the silencing of BAG3 in human OSCC cells.

Fernández-Blanco C, Frizzell C, Shannon M, et al.
An in vitro investigation on the cytotoxic and nuclear receptor transcriptional activity of the mycotoxins fumonisin B1 and beauvericin.
Toxicol Lett. 2016; 257:1-10 [PubMed] Related Publications
Fumonisin B1 (FB1) and beauvericin (BEA) are secondary metabolites of filamentous fungi, which under appropriate temperature and humidity conditions may develop on various foods and feeds. To date few studies have been performed to evaluate the toxicological and endocrine disrupting effects of FB1 and BEA. The present study makes use of various in vitro bioassays including; oestrogen, androgen, progestagen and glucocorticoid reporter gene assays (RGAs) for the study of nuclear receptor transcriptional activity, the thiazolyl blue tetrazolium bromide (MTT) assay to monitor cytotoxicity and high content analysis (HCA) for the detection of pre-lethal toxicity in the RGA and Caco-2 human colon adenocarcinoma cells. At the receptor level, 0.001-10μM BEA or FB1 did not induce any agonist responses in the RGAs. However at non-cytotoxic concentrations, an antagonistic effect was exhibited by FB1 on the androgen nuclear receptor transcriptional activity at 10μM and BEA on the progestagen and glucocorticoid receptors at 1μM. MTT analysis showed no decrease in cell viability at any concentration of FB1, whereas BEA showed a significant decrease in viability at 10μM. HCA analysis confirmed that the reduction in the progestagen receptor transcriptional activity at 1μM BEA was not due to pre-lethal toxicity. In addition, BEA (10μM) induced significant toxicity in both the TM-Luc (progestagen responsive) and Caco-2 cells.

Fang D, Gan H, Lee JH, et al.
The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas.
Science. 2016; 352(6291):1344-8 [PubMed] Related Publications
More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.

Zou Q, Cui D, Liang S, et al.
Aging up-regulates ARA55 in stromal cells, inducing androgen-mediated prostate cancer cell proliferation and migration.
J Mol Histol. 2016; 47(3):305-15 [PubMed] Related Publications
Stromal cells in the peripheral zone (PZ) of the prostate from older males (PZ-old) could significantly promote Prostate cancer (PCa) growth compared with stromal cells from young males (PZ-young). But the mechanism is still unknown. In the co-culture system with PZ-old cells, Pc3/Du145 cells showed advanced proliferation and migration after Dihydrotestosterone (DHT) incubation, but DHT didn't show the similar effect in PZ-young co-culture system. Also, higher androgen/AR signal pathway activity and AR-related cytokines secretion (FGF-2, KGF, IGF-1) were found in PZ-old cells. As AR exprssison was equivalent in PZ-old and PZ-young cells, we focused on Androgen receptor associated protein-55(ARA55), a stromal-specific androgen receptor (AR) coactivator. ARA55 expression was higher in PZ-old cells compared with PZ-young cells in vitro. After knocking down ARA55 expression in PZ-old cells, the PCa growth- promoting effect from the PZ-old cells was diminished, which may be explained by the decreased the progressive cytokines secretion (FGF-2, KGF, IGF-1) from PZ-old stromal cells. In vivo, the consistent results were also found: PZ-old cells promoted prostate cancer cells growth, but this effect receded when knocking down ARA55 expression in PZ-old cells. From our study, we found PZ stromal cells presented age-related effects in proliferation and migration of prostate cancer cells in the androgen/AR dependent manner. As aging increased, more ARA55 were expressed in PZ stromal cells, leading to more sensitive androgen/androgen receptor (AR) signal pathway, then constituting a more feasible environment to cancer cells.

Zhang H, Tsang JY, Ni YB, et al.
Hyaluronan synthase 2 is an adverse prognostic marker in androgen receptor-negative breast cancer.
J Clin Pathol. 2016; 69(12):1055-1062 [PubMed] Related Publications
AIMS: The important role of hyaluronan synthase 2 (HAS2), an isozyme responsible for hyaluronan synthesis, in cancer has been increasingly recognised. However, only a few studies with inconsistent results have been reported in breast cancers. With a large cohort, we aim to determine the clinical significance of HAS2 in breast cancers.
METHODS: We examined HAS2 expression in 1142 breast cancers using immunohistochemistry.
RESULTS: HAS2 was associated with both prognostically favourable (androgen receptor (AR), p<0.001) and unfavourable (basal and epithelial mesenchymal transition markers, p≤0.039) biomarkers. In addition, HAS2 showed differential associations with various features and outcome between AR+ and AR- subgroups. HAS2+AR- breast cancers showed significantly worse outcome than other subgroups, and HAS2+AR- subgroup was an independent adverse prognostic factor for disease-free survival (HR 1.309, p=0.046). Interestingly, HAS2 was associated with many poor prognostic features (including higher grade, lymphovascular invasion, basal-like breast cancer subtype, high Ki67 and basal marker expression) only in AR-, but not AR+ breast cancers.
CONCLUSIONS: HAS2 has been proposed to be a target for therapeutic intervention in cancer. Our findings suggested a possible antagonistic role of AR pathway on HAS2 function. It will be interesting to further investigate their precise interaction, which may have important implication in HAS2 targeting.

Wyatt AW, Azad AA, Volik SV, et al.
Genomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant Prostate Cancer.
JAMA Oncol. 2016; 2(12):1598-1606 [PubMed] Article available free on PMC after 01/12/2017 Related Publications
Importance: The molecular landscape underpinning response to the androgen receptor (AR) antagonist enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) is undefined. Consequently, there is an urgent need for practical biomarkers to guide therapy selection and elucidate resistance. Although tissue biopsies are impractical to perform routinely in the majority of patients with mCRPC, the analysis of plasma cell-free DNA (cfDNA) has recently emerged as a minimally invasive method to explore tumor characteristics.
Objective: To reveal genomic characteristics from cfDNA associated with clinical outcomes during enzalutamide treatment.
Design, Setting, and Participants: Plasma samples were obtained from August 4, 2013, to July 31, 2015, at a single academic institution (British Columbia Cancer Agency) from 65 patients with mCRPC. We collected temporal plasma samples (at baseline, 12 weeks, end of treatment) for circulating cfDNA and performed array comparative genomic hybridization copy number profiling and deep AR gene sequencing. Samples collected at end of treatment were also subjected to targeted sequencing of 19 prostate cancer-associated genes.
Exposure: Enzalutamide, 160 mg, daily orally.
Main Outcomes and Measures: Prostate-specific antigen response rate (decline ≥50% from baseline confirmed ≥3 weeks later). Radiographic (as per Prostate Cancer Working Group 2 Criteria) and/or clinical progression (defined as worsening disease-related symptoms necessitating a change in anticancer therapy and/or deterioration in Eastern Cooperative Group performance status ≥2 levels).
Results: The 65 patients had a median (interquartile range) age of 74 (68-79) years. Prostate-specific antigen response rate to enzalutamide treatment was 38% (25 of 65), while median clinical/radiographic progression-free survival was 3.5 (95% CI, 2.1-5.0) months. Cell-free DNA was isolated from 122 of 125 plasma samples, and targeted sequencing was successful in 119 of 122. AR mutations and/or copy number alterations were robustly detected in 48% (31 of 65) and 60% (18 of 30) of baseline and progression samples, respectively. Detection of AR amplification, heavily mutated AR (≥2 mutations), and RB1 loss were associated with worse progression-free survival, with hazard ratios of 2.92 (95% CI, 1.59-5.37), 3.94 (95% CI, 1.46-10.64), and 4.46 (95% CI, 2.28-8.74), respectively. AR mutations exhibited clonal selection during treatment, including an increase in glucocorticoid-sensitive AR L702H and promiscuous AR T878A in patients with prior abiraterone treatment. At the time of progression, cfDNA sequencing revealed mutations or copy number changes in all patients tested, including clinically actionable alterations in DNA damage repair genes and PI3K pathway genes, and a high frequency (4 of 14) of activating CTNNB1 mutations.
Conclusions and Relevance: Clinically informative genomic profiling of cfDNA was feasible in nearly all patients with mCRPC and can provide important insights into enzalutamide response and resistance.

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