TMPRSS2

Gene Summary

Gene:TMPRSS2; transmembrane serine protease 2
Aliases: PP9284, PRSS10
Location:21q22.3
Summary:This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, a receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Serine proteases are known to be involved in many physiological and pathological processes. This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transmembrane protease serine 2
Source:NCBIAccessed: 29 August, 2019

Ontology:

What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 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.

  • ROC Curve
  • Transcriptional Regulator ERG
  • alpha Karyopherins
  • Prostate Cancer
  • Immunohistochemistry
  • Cell Proliferation
  • Protein Array Analysis
  • Prostatectomy
  • Urinalysis
  • Up-Regulation
  • Prostate
  • Tissue Array Analysis
  • Cancer Gene Expression Regulation
  • ERG
  • Gene Fusion
  • Gene Rearrangement
  • Sarcosine
  • Trans-Activators
  • TMPRSS2
  • Staging
  • Gene Expression Profiling
  • Proteomics
  • FISH
  • Prostate-Specific Antigen
  • Disease Progression
  • Biomarkers, Tumor
  • Radiotherapy, Image-Guided
  • Messenger RNA
  • Oncogene Fusion Proteins
  • Recurrence
  • Adenocarcinoma
  • Estrogen Receptors
  • PTEN
  • Prostatic Neoplasms, Castration-Resistant
  • Tosyl Compounds
  • Translocation
  • ETV1
  • Chromosome 21
  • Neoplasm Grading
  • Proto-Oncogene Proteins c-ets
  • Transcriptome
  • Tubulin
  • Ultraviolet Rays
  • Synaptophysin
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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

Entity Topic PubMed Papers
Prostate CancerTMPRSS2 and Prostate Cancer View Publications534
Prostate CancerETV1 translocations in Prostate Cancer
Gene fusions involving the erythroblast transformation-specific (ETS) transcription factors ERG, ETV1, ETV4, ETV5, and FLI1 are a common feature of prostate carcinomas. Most frequently, the androgen-activated gene TMPRSS2 is fused to the ERG gene, but less frequently involving ETV1, ETV4 ,ETV5 and over 12 fusion partners identified so far.
View Publications99
Prostate CancerERG-TMPRSS2 Fusion in Prostate Cancer
The fusion of ERG and TMPRSS2 (21q22.3) is common in prostate cancer. It may be caused by intronic deletion or translocation.
See: More details below...

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

ERG-TMPRSS2 Fusion in Prostate Cancer

The fusion of ERG and TMPRSS2 (21q22.3) is common in prostate cancer. It may be caused by intronic deletion or translocation.

See also: Prostate Cancer - Clinical and Research information
See also: TMPRSS2.htm gene

Latest Publications

Lee RS, Zhang L, Berger A, et al.
Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target.
Neoplasia. 2019; 21(4):389-400 [PubMed] Free Access to Full Article Related Publications
Approximately 50% of prostate cancers harbor the TMPRSS2:ERG fusion, resulting in elevated expression of the ERG transcription factor. Despite the identification of this subclass of prostate cancers, no personalized therapeutic strategies have achieved clinical implementation. Kinases are attractive therapeutic targets as signaling networks are commonly perturbed in cancers. The impact of elevated ERG expression on kinase signaling networks in prostate cancer has not been investigated. Resolution of this issue may identify novel therapeutic approaches for ERG-positive prostate cancers. In this study, we used quantitative mass spectrometry-based kinomic profiling to identify ERG-mediated changes to cellular signaling networks. We identified 76 kinases that were differentially expressed and/or phosphorylated in DU145 cells engineered to express ERG. In particular, the Traf2 and Nck-interacting kinase (TNIK) was markedly upregulated and phosphorylated on multiple sites upon ERG overexpression. Importantly, TNIK has not previously been implicated in prostate cancer. To validate the clinical relevance of these findings, we characterized expression of TNIK and TNIK phosphorylated at serine 764 (pS764) in a localized prostate cancer patient cohort and showed that nuclear enrichment of TNIK (pS764) was significantly positively correlated with ERG expression. Moreover, TNIK protein levels were dependent upon ERG expression in VCaP cells and primary cells established from a prostate cancer patient-derived xenograft. Furthermore, reduction of TNIK expression and activity by silencing TNIK expression or using the TNIK inhibitor NCB-0846 reduced cell viability, colony formation and anchorage independent growth. Therefore, TNIK represents a novel and actionable therapeutic target for ERG-positive prostate cancers that could be exploited to develop new treatments for these patients.

Gerashchenko GV, Grygoruk OV, Kononenko OA, et al.
Expression pattern of genes associated with tumor microenvironment in prostate cancer.
Exp Oncol. 2018; 40(4):315-322 [PubMed] Related Publications
AIM: To assess relative expression (RE) levels of CAF-, TAM-specific, immune defense-associated genes in prostate tumors and to show correlation of RE with clinical, pathological and molecular characteristics, with the aim to define clinically significant specific alterations in a gene expression pattern.
METHODS: RE of 23 genes was analyzed by a quantitative polymerase chain reaction in 37 freshly frozen samples of prostate cancer tissues of a different Gleason score (GS) and at various tumor stages, compared with RE in 37 paired conventionally normal prostate tissue (CNT) samples and 20 samples of prostate adenomas.
RESULTS: Differences in RE were shown for 11 genes out of 23 studied, when tumor samples were compared with corresponding CNTs. 7 genes, namely ACTA2, CXCL14, CTGF, THY1, FAP, CD163, CCL17 were upregulated in tumors. 4 genes, namely CCR4, NOS2A, MSMB, IL1R1 were downregulated in tumors. 14 genes demonstrated different RE in TNA at different stages: CXCL12, CXCL14, CTGF, FAP, HIF1A, THY1, CCL17, CCL22, CCR4, CD68, CD163, NOS2A, CTLA4, IL1R1. RE changes of 9 genes - CXCL12, CXCL14, HIF1A, CCR4, CCL17, NOS2A, CTLA4, IL1R1, IL2RA - were found in tumors with different GS. Moreover, 9 genes showed differences in RE in TNA, dependently on the presence or absence of the TMPRSS2/ERG fusion and 7 genes showed differences in RE of groups with differential PTEN expression. Significant correlations were calculated between RE of 9 genes in adenocarcinomas and the stage, and GS; also, between RE of 2 genes and the fusion presence; and between RE of 4 genes and PTEN expression.
CONCLUSIONS: Several gene expression patterns were identified that correlated with the GS, stage and molecular characteristics of tumors, i.e. presence of the TMPRSS2/ERG fusion and alterations in PTEN expression. These expression patterns can be used for molecular profiling of prostate tumors, with the aim to develop personalized medicine approaches. However, the proposed profiling requires a more detailed analysis and a larger cohort of patients with prostate tumor.

Jin ML, Kim YW, Jeong KW
BAF53A regulates androgen receptor-mediated gene expression and proliferation in LNCaP cells.
Biochem Biophys Res Commun. 2018; 505(2):618-623 [PubMed] Related Publications
The actin-like protein of the SWI/SNF complex, BAF53A, regulates gene expression by the gene-specific chromatin remodeling of target genes. However, the function of BAF53A in the androgen receptor pathway in prostate cancer cells remains unclear. Here, we demonstrated that BAF53A positively regulates the expression of endogenous AR target genes (e.g. PSA, TMPRSS2, FKBP5, and KLK2) in LNCaP cells. It functions as a coactivator in AR-mediated transcription by interacting with other nuclear receptor coactivators, such as p300 and FLII, and is associated with AR in the presence of dihydrotestosterone (DHT). The DHT-induced recruitment of BAF53A to the proximal and distal androgen response elements (AREs) of the PSA gene in the presence of BRG1 (but not BRM) was inhibited by an AR antagonist, suggesting the coactivator function of BAF53A in the SWI/SNF complex. Depletion of BAF53A in LNCaP cells resulted in a significant decrease in growth rate. Furthermore, the expression of BAF53A in prostate cancer tissue was significantly elevated, compared to that in normal prostate tissue, and correlated with the expression of AR, and BRG1, but not BRM. Therefore, our results suggested that BAF53A plays an important role in the expression of AR target genes in prostate cancer, and can be used clinically for the treatment of prostate cancer.

Wang S, Zhang Q, Xu D, et al.
Characterize the difference between TMPRSS2-ERG and non-TMPRSS2-ERG fusion patients by clinical and biological characteristics in prostate cancer.
Gene. 2018; 679:186-194 [PubMed] Related Publications
The TMPRSS2-ERG gene fusion were frequently found in prostate cancer, and thought to play some fundamental mechanisms for the development of prostate cancer. However, until now, the clinical and prognostic significance of TMPRSS2-ERG gene fusion was not fully understood. In this study, based on the 281 prostate cancers that constructed from a historical watchful waiting cohort, the statistically significant associations between TMPRSS2-ERG gene fusion and clinicopathologic characteristics were identified. In addition, the Elastic Net algorithm was used to predict the patients with TMPRSS2-ERG fusion status, and good predictive results were obtained, indicating that this algorithm was suitable to this prediction problem. The differential gene network was constructed from the network, and the KEGG enrichment analysis demonstrated that the module genes were significantly enriched in several important pathways.

Ahearn TU, Peisch S, Pettersson A, et al.
Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease.
Carcinogenesis. 2018; 39(12):1431-1437 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Frank S, Nelson P, Vasioukhin V
Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects.
F1000Res. 2018; 7 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Prostate cancer (PCa) is a disease of mutated and misregulated genes. However, primary prostate tumors have relatively few mutations, and only three genes (

Sandoval GJ, Pulice JL, Pakula H, et al.
Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis.
Mol Cell. 2018; 71(4):554-566.e7 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

Xu Z, Wang Y, Xiao ZG, et al.
Nuclear receptor ERRα and transcription factor ERG form a reciprocal loop in the regulation of TMPRSS2:ERG fusion gene in prostate cancer.
Oncogene. 2018; 37(48):6259-6274 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
The TMPRSS2:ERG (T:E) fusion gene is generally believed to be mainly regulated by the activated androgen receptor (AR) signaling in androgen-dependent prostate cancer. However, its persistent expression in castration-resistant and neuroendocrine prostate cancers implies that other transcription factors might also regulate its expression. Here, we showed that up-regulation of nuclear receptor estrogen-related receptor alpha (ERRα) was closely associated with the oncogenic transcription factor ERG expression in prostate cancer, and their increased coexpression patterns were closely associated with high Gleason scores and metastasis in patients. Both ERRα and ERG exhibited a positive expression correlation in a castration-resistant prostate cancer (CRPC) xenograft model VCaP-CRPC. We showed that ERRα could directly transactivate T:E fusion gene in both AR-positive and -negative prostate cancer cells via both ERR-binding element- and AR-binding element-dependent manners. Ectopic T:E expression under ERRα regulation could promote both in vitro invasion and in vivo metastasis capacities of AR-negative prostatic cells. Intriguingly, ERG expressed by the T:E fusion could also transactivate the ERRα (ESRRA) gene. Hereby, ERRα and ERG can synergistically regulate each other and form a reciprocal regulatory loop to promote the advanced growth of prostate cancer. Inhibition of ERRα activity by ERRα inverse agonist could suppress T:E expression in prostate cancer cells, implicating that targeting ERRα could be a potential therapeutic strategy for treating the aggressive T:E-positive prostate cancer.

Gerashchenko GV, Mevs LV, Chashchina LI, et al.
Expression of steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion.
Exp Oncol. 2018; 40(2):101-108 [PubMed] Related Publications
AIM: To analyze an expression pattern of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion; and to examine a putative correlation between gene expression and clinical characteristics, to define the molecular subtypes of prostate cancer.
MATERIALS AND METHODS: The relative gene expression (RE) of 33 transcripts (27 genes) and the presence/absence of the TMPRSS2/ERG fusion were analyzed by a quantitative PCR. 37 prostate cancer tissues (T) paired with conventionally normal prostate tissue (CNT) and 21 samples of prostate adenomas were investigated. RE changes were calculated, using different protocols of statistics.
RESULTS: We demonstrated differences in RE of seven genes between tumors and CNT, as was calculated, using the 2-ΔCT model and the Wilcoxon matched paired test. Five genes (ESR1, KRT18, MKI67, MMP9, PCA3) showed altered expression in adenocarcinomas, in which the TMPRSS2/ERG fusion was detected. Two genes (INSR, isoform B and HOTAIR) expressed differently in tumors without fusion. Comparison of the gene expression pattern in adenomas, CNT and adenocarcinomas demonstrated that in adenocarcinomas, bearing the TMPRSS2/ERG fusion, genes KRT18, PCA3, and SCHLAP1 expressed differently. At the same time, we detected differences in RE of AR (isoform 2), MMP9, PRLR and HOTAIR in adenocarcinomas without the TMPRSS2/ERG fusion. Two genes (ESR1 and SRD5A2) showed differences in RE in both adenocarcinoma groups. Fourteen genes, namely AR (isoforms 1 and 2), CDH1, OCLN, NKX3-1, XIAP, GCR (ins AG), INSR (isoform A), IGF1R, IGF1R tr, PRLR, PRL, VDR and SRD5A2 showed correlation between RE and tumor stage. RE of four genes (CDH2, ESR2, VDR and SRD5A2) correlated with differentiation status of tumors (Gleason score). Using the K-means clustering, we could cluster adenocarcinomas in three groups, according to gene expression profiles. A specific subtype of prostate tumors is characterized by the activated ERG signaling, due to the presence of TMPRSS2/ERG fusion, and also by high levels of the androgen receptor, prolactin, IGF, INSR and PCA3.
CONCLUSIONS: We have found the specific differences in expression of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes, depending on the pre-sence/absence of the TMPRSS2/ERG fusion in prostate adenocarcinomas, CNT and adenomas. We showed three different gene expression profiles of prostate adenocarcinomas. One of them is characteristic for adenocarcinomas with the TMPRSS2/ERG fusion. Further experiments are needed to confirm these data in a larger cohort of patients.

Lee SR, Choi YD, Cho NH
Association between pathologic factors and ERG expression in prostate cancer: finding pivotal networking.
J Cancer Res Clin Oncol. 2018; 144(9):1665-1683 [PubMed] Related Publications
PURPOSE: To evaluate associations between pathologic factors and erythroblast transformation-specific (ETS)-related gene (ERG) expression in prostate cancer patients. Using next-generation sequencing, we identified target genes and regulatory networks.
METHODS: ERG expression in 60 radical prostatectomies was compared with pathological findings by association rule mining with the Apriori algorithm. Whole-exome and RNA sequencing were performed on three formalin-fixed, paraffin-embedded ERG-positive and negative prostate cancer samples. A network diagram identifying dominant altered genes was constructed using Cytoscape open-source bioinformatics platform and GeneMania plugin.
RESULTS: Pathologic conditions positive for perineural invasion, apical margins, and Gleason score 3 + 4 = 7 were significantly more likely to be ERG-positive than other pathologic conditions (p = 0.0008), suggesting an association between ERG positivity, perineural invasion, apical margins, and Gleason score 3 + 4 = 7 (Firth's logistic regression: OR 42.565, 95% CI 1.670-1084.847, p = 0.0232). Results of whole-exome and RNA sequencing identified 97 somatic mutations containing common mutated genes. Regulatory network analysis identified NOTCH1, MEF2C, STAT3, LCK, CACNA2D3, PCSK7, MEF2A, PDZD2, TAB1, and ASGR1 as pivotal genes. NOTCH1 appears to function as a hub, because it had the highest node degree and betweenness. NOTCH1 staining was found 8 of 60 specimens (13%), with a significant association between ERG and NOTCH1 positivity (p = 0.001).
CONCLUSIONS: Evaluating the association between ERG expression and pathologic factors, and identifying the regulatory network and pivotal hub may help to understand the clinical significance of ERG-positive prostate cancer.

Pakula H, Linn DE, Schmidt DR, et al.
Protocols for Studies on TMPRSS2/ERG in Prostate Cancer.
Methods Mol Biol. 2018; 1786:131-151 [PubMed] Related Publications
TMPRSS2/ERG is the most common type of gene fusions found in human prostate cancer. There are two important features of TMPRSS2/ERG fusions. One is that these gene fusions lead to ectopic expression of ERG, an ETS family transcription factor, in prostate epithelial cells from the 5' control region of an androgen/estrogen dual-responsive gene, TMPRSS2; the other is that ~60% of these fusions are generated via intrachromosomal deletion of the interstitial region between TMPRSS2 and ERG. To recapitulate these important aspects of TMPRSS2/ERG fusions, we generated several TMPRSS2/ERG knockin mouse models based on the endogenous Tmprss2 locus. We found that TMPRSS2/ERG represents an early event in prostate tumorigenesis, by sensitizing prostate cells for cooperation with other oncogenic events, such as PTEN-deficiency. We also found that the interstitial region between TMPRSS2 and ERG harbors at least one prostate tumor suppressor, ETS2, whose loss contributes to prostate cancer progression. In this protocol, we describe how these knockin mouse models can be utilized to study roles of TMPRSS2/ERG fusions in prostate cancer development both in vivo and in vitro.

Knuuttila M, Mehmood A, Mäki-Jouppila J, et al.
Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer.
Endocr Relat Cancer. 2018; 25(9):807-819 [PubMed] Related Publications
Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate (

Hinsch A, Brolund M, Hube-Magg C, et al.
Immunohistochemically detected IDH1
World J Urol. 2018; 36(6):877-882 [PubMed] Related Publications
BACKGROUND: IDH1 mutations are oncogenic through induction of DNA damage and genome instability. They are of therapeutic interest because they confer increased sensitivity to radiation and cytotoxic therapy and hold potential for vaccination therapy.
METHODS: In this study, we analyzed more than 17,000 primary prostate cancer tissues with a mutation-specific antibody for the IDH1
RESULTS: IDH1 mutation-specific staining was found in 42 of 15,531 (0.3%) interpretable cancers. IDH1 mutation was associated with higher preoperative PSA and Gleason grade (p < 0.05, each) but was unrelated to PSA recurrence. A comparison with other molecular tumor features available from earlier studies revealed that TMPRSS2-ERG fusion as well as deletion of PTEN, 5q21, 6q15, and 3p13 was less frequent in IDH1-mutated than in non-mutated cancer. Increased lethality of genetically instable, "aberration-rich" cancer cells in the presence of IDH1 mutations could possibly explain this observation. Heterogeneity analysis revealed a homogeneous mutation in only 1 of 16 IDH1-mutated cancers. This high degree of heterogeneity may profoundly limit therapeutic targeting of IDH1 mutations in prostate cancer.
CONCLUSIONS: The data show that 0.3% of prostate cancers have an IDH1

Li X, Baek G, Ramanand SG, et al.
BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer.
Cell Rep. 2018; 22(3):796-808 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
BRD4 belongs to the bromodomain and extraterminal (BET) family of chromatin reader proteins that bind acetylated histones and regulate gene expression. Pharmacological inhibition of BRD4 by BET inhibitors (BETi) has indicated antitumor activity against multiple cancer types. We show that BRD4 is essential for the repair of DNA double-strand breaks (DSBs) and mediates the formation of oncogenic gene rearrangements by engaging the non-homologous end joining (NHEJ) pathway. Mechanistically, genome-wide DNA breaks are associated with enhanced acetylation of histone H4, leading to BRD4 recruitment, and stable establishment of the DNA repair complex. In support of this, we also show that, in clinical tumor samples, BRD4 protein levels are negatively associated with outcome after prostate cancer (PCa) radiation therapy. Thus, in addition to regulating gene expression, BRD4 is also a central player in the repair of DNA DSBs, with significant implications for cancer therapy.

Gu JL, Chukhman M, Lu Y, et al.
RNA-seq Based Transcription Characterization of Fusion Breakpoints as a Potential Estimator for Its Oncogenic Potential.
Biomed Res Int. 2017; 2017:9829175 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Based on high-throughput sequencing technology, the detection of gene fusions is no longer a big challenge but estimating the oncogenic potential of fusion genes remains challenging. Recent studies successfully applied machine learning methods and gene structural and functional features of fusion mutation to predict their oncogenic potentials. However, the transcription characterizations features of fusion genes have not yet been studied. In this study, based on the clonal evolution theory, we hypothesized that a fusion gene is more likely to be an oncogenic genomic alteration, if the neoplastic cells harboring this fusion mutation have larger clonal size than other neoplastic cells in a tumor. We proposed a novel method, called iFCR (internal Fusion Clone Ratio), given an estimation of oncogenic potential for fusion mutations. We have evaluated the iFCR method in three public cancer transcriptome sequencing datasets; the results demonstrated that the fusion mutations occurring in tumor samples have higher internal fusion clone ratio than normal samples. And the most frequent prostate cancer fusion mutation, TMPRSS2-ERG, appears to have a remarkably higher iFCR value in all three independent patients. The preliminary results suggest that the internal fusion clone ratio might potentially advantage current fusion mutation oncogenic potential prediction methods.

Chu K, Corcoran N, Norden S, Wong LM
New Histopathological & Genetic Features to Improve Active Surveillance Selection for Low-Risk Prostate Cancer.
Anticancer Agents Med Chem. 2018; 18(7):951-957 [PubMed] Related Publications
BACKGROUND: A recent surge in biomarkers to aid management of men with prostate cancer has occurred. Their applications are varied and not all tests are applicable to the active surveillance setting.
OBJECTIVE: To review primary evidence on genetic and immunohistochemical biomarkers, and their role on patient selection and risk stratification for men on active surveillance for prostate cancer.
EVIDENCE ACQUISITION: A PubMed electronic search using the terms (biomarker or genetic or histopathological) AND ("prostate cancer" AND "active surveillance") was performed from inception to April 2015.
EVIDENCE SYNTHESIS: Of the biomarkers reviewed, Prostate Health Index (PHI) and Oncotype DX Genomic Prostate Score (GPS), were identified to currently hold greatest potential benefit to aid risk stratification of men for AS. Higher PHI, at baseline and during follow-up, was shown to predict pathological upgrading at rebiopsy at two single institutions, but with small cohorts (n<200). The Oncotype DX GPS test has been validated on men suitable for AS but having upfront radical prostatectomy. Increase in GPS was shown to predict upgrading and upstaging at radical prostatectomy and biochemical recurrence post radical prostatectomy. Prospective validation in AS cohorts is yet to be performed.
CONCLUSIONS: PHI and Oncotype DX GPS show promise in aiding risk stratification for men on AS. However, larger prospective studies in AS cohorts are needed. Integration of biomarkers with existing clinical and imaging models remains a challenge.

Murphy SJ, Kosari F, Karnes RJ, et al.
Retention of Interstitial Genes between
Cancer Res. 2017; 77(22):6157-6167 [PubMed] Related Publications

Yang Y, Blee AM, Wang D, et al.
Loss of FOXO1 Cooperates with TMPRSS2-ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion.
Cancer Res. 2017; 77(23):6524-6537 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
E26 transformation-specific transcription factor ERG is aberrantly overexpressed in approximately 50% of all human prostate cancer due to

Babu D, Fullwood MJ
Expanding the effects of ERG on chromatin landscapes and dysregulated transcription in prostate cancer.
Nat Genet. 2017; 49(9):1294-1295 [PubMed] Related Publications
ERG overexpression in prostate cancers promotes the development of widespread changes in gene expression and chromatin landscapes, leading to redistribution of key transcription factors in prostate cancers positive for the TMPRSS2-ERG fusion gene. The overexpression of ERG is further assisted by the development of a super-enhancer in the ERG locus.

Wang Z, Wang Y, Zhang J, et al.
Significance of the TMPRSS2:ERG gene fusion in prostate cancer.
Mol Med Rep. 2017; 16(4):5450-5458 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
The transmembrane protease serine 2:v‑ets erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion is common in prostate cancer, while its functional role is not fully understood. The present study aimed to investigate the significance of the TMPRSS2:ERG gene fusion in human prostate cancers using bioinformatics tools. Comprehensive alteration analysis of TMPRSS2 and ERG in 148 different human cancer studies was performed by cBioPortal, and the mRNA expression level of the ERG gene was evaluated using Oncomine analysis. Furthermore, lentiviral short hairpin (sh)RNA‑mediated knockdown of TMPRSS2:ERG was performed to study the impact of ERG silencing on cell proliferation and cell cycle distribution in prostate cancer cells. The results demonstrated that the TMPRSS2 and ERG genes were mostly altered in prostate cancer, and the most frequent alteration was gene fusion. Oncomine analysis demonstrated that the ERG gene was significantly upregulated in prostate clinical samples compared with the normal prostate gland in four independent datasets, and a positive association was observed between potassium inwardly‑rectifying channel subfamily J member 15, down syndrome critical region gene 4, potassium inwardly‑rectifying channel subfamily J member 6 and ERG gene expression. There were 272 mutations of the ERG gene identified in the cBioPortal database; among the mutations, 2 missense mutations (R367C and P401H) were regarded as functional mutations (functional impact score >1.938). Furthermore, the present study successfully knocked down ERG gene expression through a lentiviral‑mediated gene silencing approach in VCaP prostate cancer cells. The ERG mRNA and protein expression levels were both suppressed significantly, and a cell‑cycle arrest at G0/G1 phase was observed after ERG gene silencing. In conclusion, these bioinformatics analyses provide novel insights for TMPRSS2:ERG fusion gene study in prostate cancer. Target inhibition of ERG expression could significantly cause cell growth arrest in prostate cancer cells, which could be a potentially valuable target for prostate cancer treatment. However, the precise mechanism of these results remains unclear; therefore, further studies are required.

Latest Publications: TMPRSS2 (cancer-related)

Lee RS, Zhang L, Berger A, et al.
Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target.
Neoplasia. 2019; 21(4):389-400 [PubMed] Free Access to Full Article Related Publications
Approximately 50% of prostate cancers harbor the TMPRSS2:ERG fusion, resulting in elevated expression of the ERG transcription factor. Despite the identification of this subclass of prostate cancers, no personalized therapeutic strategies have achieved clinical implementation. Kinases are attractive therapeutic targets as signaling networks are commonly perturbed in cancers. The impact of elevated ERG expression on kinase signaling networks in prostate cancer has not been investigated. Resolution of this issue may identify novel therapeutic approaches for ERG-positive prostate cancers. In this study, we used quantitative mass spectrometry-based kinomic profiling to identify ERG-mediated changes to cellular signaling networks. We identified 76 kinases that were differentially expressed and/or phosphorylated in DU145 cells engineered to express ERG. In particular, the Traf2 and Nck-interacting kinase (TNIK) was markedly upregulated and phosphorylated on multiple sites upon ERG overexpression. Importantly, TNIK has not previously been implicated in prostate cancer. To validate the clinical relevance of these findings, we characterized expression of TNIK and TNIK phosphorylated at serine 764 (pS764) in a localized prostate cancer patient cohort and showed that nuclear enrichment of TNIK (pS764) was significantly positively correlated with ERG expression. Moreover, TNIK protein levels were dependent upon ERG expression in VCaP cells and primary cells established from a prostate cancer patient-derived xenograft. Furthermore, reduction of TNIK expression and activity by silencing TNIK expression or using the TNIK inhibitor NCB-0846 reduced cell viability, colony formation and anchorage independent growth. Therefore, TNIK represents a novel and actionable therapeutic target for ERG-positive prostate cancers that could be exploited to develop new treatments for these patients.

Şükrüoğlu Erdoğan Ö, Kılıç Erciyas S, Bilir A, et al.
Methylation Changes of Primary Tumors, Monolayer, and Spheroid Tissue Culture Environments in Malignant Melanoma and Breast Carcinoma.
Biomed Res Int. 2019; 2019:1407167 [PubMed] Free Access to Full Article Related Publications
Epigenetic changes have major role in the normal development and programming of gene expression. Aberrant methylation results in carcinogenesis. The primary objective of our study is to determine whether primary tumor tissue and cultured tumor cells in 2D and 3D tissue culture systems have the same methylation signature for

Ormond DR, Kleinschmidt-DeMasters BK, Cavalcante D, et al.
Prostatic adenocarcinoma CNS parenchymal and dural metastases: alterations in ERG, CHD1 and MAP3K7 expression.
J Neurooncol. 2019; 142(2):319-325 [PubMed] Related Publications
BACKGROUND: Prostatic carcinoma metastatic to dura is commonly encountered at autopsy, but presenting as a dural or, especially parenchymal, brain metastasis during life is far less common. Our group has been interested in two immunohistochemical (IHC) markers previously shown to be downregulated in particularly aggressive primary prostatic carcinomas: CHD1 and MAP3K7. Here we assess protein expression in clinically-relevant CNS metastases. We also assessed how these two markers correlated with the most common genetic alteration in prostate cancer: TMPRSS2 fusion to ERG (40-60% of carcinomas at the primary site), which places ERG expression under the control of the androgen-regulated TMPRSS2 gene, increasing expression.
DESIGN: Database query, 2000-2016, identified 16 metastases to dura, 5 to brain parenchyma.
RESULTS: Four of five intraparenchymal metastases and 15/16 informative dural-based metastases were ERG-negative (90.5% overall). There was reduced expression of CHD1 in 8/21 and reduced MAP3K7 in 17/21 cases; 7/19 (37%) ERG-negative metastases had dual low expression of CHD1/MAP3K7. ERG-positive cases had high expression of one or both markers.
CONCLUSION: Metastatic prostatic carcinoma to CNS demonstrates expression patterns consistent with particularly aggressive behavior. Lower ERG expression in dural and intraparenchymal metastases suggests a possibility that ERG-negative tumors with loss of MAP3K7 may become resistant to standard therapies and diffusely metastasize.

Gerashchenko GV, Grygoruk OV, Kononenko OA, et al.
Expression pattern of genes associated with tumor microenvironment in prostate cancer.
Exp Oncol. 2018; 40(4):315-322 [PubMed] Related Publications
AIM: To assess relative expression (RE) levels of CAF-, TAM-specific, immune defense-associated genes in prostate tumors and to show correlation of RE with clinical, pathological and molecular characteristics, with the aim to define clinically significant specific alterations in a gene expression pattern.
METHODS: RE of 23 genes was analyzed by a quantitative polymerase chain reaction in 37 freshly frozen samples of prostate cancer tissues of a different Gleason score (GS) and at various tumor stages, compared with RE in 37 paired conventionally normal prostate tissue (CNT) samples and 20 samples of prostate adenomas.
RESULTS: Differences in RE were shown for 11 genes out of 23 studied, when tumor samples were compared with corresponding CNTs. 7 genes, namely ACTA2, CXCL14, CTGF, THY1, FAP, CD163, CCL17 were upregulated in tumors. 4 genes, namely CCR4, NOS2A, MSMB, IL1R1 were downregulated in tumors. 14 genes demonstrated different RE in TNA at different stages: CXCL12, CXCL14, CTGF, FAP, HIF1A, THY1, CCL17, CCL22, CCR4, CD68, CD163, NOS2A, CTLA4, IL1R1. RE changes of 9 genes - CXCL12, CXCL14, HIF1A, CCR4, CCL17, NOS2A, CTLA4, IL1R1, IL2RA - were found in tumors with different GS. Moreover, 9 genes showed differences in RE in TNA, dependently on the presence or absence of the TMPRSS2/ERG fusion and 7 genes showed differences in RE of groups with differential PTEN expression. Significant correlations were calculated between RE of 9 genes in adenocarcinomas and the stage, and GS; also, between RE of 2 genes and the fusion presence; and between RE of 4 genes and PTEN expression.
CONCLUSIONS: Several gene expression patterns were identified that correlated with the GS, stage and molecular characteristics of tumors, i.e. presence of the TMPRSS2/ERG fusion and alterations in PTEN expression. These expression patterns can be used for molecular profiling of prostate tumors, with the aim to develop personalized medicine approaches. However, the proposed profiling requires a more detailed analysis and a larger cohort of patients with prostate tumor.

Stelloo S, Nevedomskaya E, Kim Y, et al.
Integrative epigenetic taxonomy of primary prostate cancer.
Nat Commun. 2018; 9(1):4900 [PubMed] Free Access to Full Article Related Publications
The Androgen Receptor (AR) is the key-driving transcription factor in prostate cancer, tightly controlled by epigenetic regulation. To date, most epigenetic profiling has been performed in cell lines or limited tissue samples. Here, to comprehensively study the epigenetic landscape, we perform RNA-seq with ChIP-seq for AR and histone modification marks (H3K27ac, H3K4me3, H3K27me3) in 100 primary prostate carcinomas. Integrative molecular subtyping of the five data streams revealed three major subtypes of which two were clearly TMPRSS2-ERG dictated. Importantly, we identify a third subtype with low chromatin binding and activity of AR, but with high activity of FGF and WNT signaling. While positive for neuroendocrine-hallmark genes, these tumors were copy number-neutral with low mutational burden, significantly depleted for genes characteristic of poor-outcome associated luminal B-subtype. We present a unique resource on transcriptional and epigenetic control in prostate cancer, revealing tight control of gene regulation differentially dictated by AR over three subtypes.

Hernandez J, Gelfond J, Goros M, et al.
The effect of 3-month finasteride challenge on biomarkers for predicting cancer outcome on biopsy: Results of a randomized trial.
PLoS One. 2018; 13(10):e0204823 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Finasteride, a 5-alpha reductase inhibitor may have effects on biomarkers such as prostate-specific antigen (PSA) that could be leveraged to improve screening.
OBJECTIVE: To determine the predictive characteristics of biomarkers for prostate cancer for cancer on biopsy following 3 months of finasteride use compared with placebo.
DESIGN, SETTING AND PARTICIPANTS: 383 men from multiple clinical sites with intermediate prostate cancer risk, without history of prostate cancer, were randomly allocated in a double-blinded manner, 4:1, to receive either finasteride or placebo for 90 days at which time a prostate biopsy was performed.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were associations of biomarkers with prostate cancer that were tested using multiple logistic regression and area under the receiver operating curves (AUC). Biomarkers for PCA risk (PCA3, TMPRSS2:ERG (T2:ERG) gene product, and PSA) were measured at baseline and at biopsy in a blinded fashion to assess the predictive performance of baseline levels, 90-day levels, and measures of change relative to standard predictors.
RESULTS AND LIMITATIONS: A total of 292 (233 finasteride; 59 placebo) randomized patients underwent biopsy and were analyzed. On finasteride, baseline and 90-day measures of PCA3 and T2:ERG had similar moderate discrimination capacity with AUCs 62 to 65% (p-values < 0.001 and 0.001, respectively), but their rates of change had no discrimination ability (AUC 51%, (95% CI 43 to 60% p = 0.72) and 48% (95% CI 44 to 60%, p = 0.62), respectively).) Relative to baseline, the 90-day PCA3 and PSA decreased in the finasteride group by 25% and 50%, respectively (both p<0.001). T2:ERG had a smaller, non-significant change post finasteride treatment (p = 0.08).
CONCLUSIONS: Short-term finasteride therapy did not improve performance of the most commonly-employed prostate cancer biomarkers. Threshold values for new biomarkers of prostate cancer should be interpreted with caution in patients receiving finasteride until formal validation of test performance in these patients is conducted.
PATIENT SUMMARY: Three months of finasteride treatment did not increase the accuracy for predicting the outcome on prostate biopsy but did have a significant effect on biomarker values. Adjustments to thresholds for biopsy for men on finasteride are proposed.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01296672.

Shin SH, Lee GY, Lee M, et al.
Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway.
Nat Commun. 2018; 9(1):4113 [PubMed] Free Access to Full Article Related Publications
Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood. We here investigate a role of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain-2 (CITED2) in prostate cancer metastasis. CITED2 is highly expressed in metastatic prostate cancer, and its expression is correlated with poor survival. The CITED2 gene is highly activated by ETS-related gene that is overexpressed due to chromosomal translocation. CITED2 acts as a molecular chaperone to guide PRMT5 and p300 to nucleolin, thereby activating nucleolin. Informatics and experimental data suggest that the CITED2-nucleolin axis is involved in prostate cancer metastasis. This axis stimulates cell migration through the epithelial-mesenchymal transition and promotes cancer metastasis in a xenograft mouse model. Our results suggest that CITED2 plays a metastasis-promoting role in prostate cancer and thus could be a target for preventing prostate cancer metastasis.

Jin ML, Kim YW, Jeong KW
BAF53A regulates androgen receptor-mediated gene expression and proliferation in LNCaP cells.
Biochem Biophys Res Commun. 2018; 505(2):618-623 [PubMed] Related Publications
The actin-like protein of the SWI/SNF complex, BAF53A, regulates gene expression by the gene-specific chromatin remodeling of target genes. However, the function of BAF53A in the androgen receptor pathway in prostate cancer cells remains unclear. Here, we demonstrated that BAF53A positively regulates the expression of endogenous AR target genes (e.g. PSA, TMPRSS2, FKBP5, and KLK2) in LNCaP cells. It functions as a coactivator in AR-mediated transcription by interacting with other nuclear receptor coactivators, such as p300 and FLII, and is associated with AR in the presence of dihydrotestosterone (DHT). The DHT-induced recruitment of BAF53A to the proximal and distal androgen response elements (AREs) of the PSA gene in the presence of BRG1 (but not BRM) was inhibited by an AR antagonist, suggesting the coactivator function of BAF53A in the SWI/SNF complex. Depletion of BAF53A in LNCaP cells resulted in a significant decrease in growth rate. Furthermore, the expression of BAF53A in prostate cancer tissue was significantly elevated, compared to that in normal prostate tissue, and correlated with the expression of AR, and BRG1, but not BRM. Therefore, our results suggested that BAF53A plays an important role in the expression of AR target genes in prostate cancer, and can be used clinically for the treatment of prostate cancer.

Filella X, Foj L
Novel Biomarkers for Prostate Cancer Detection and Prognosis.
Adv Exp Med Biol. 2018; 1095:15-39 [PubMed] Related Publications
Prostate cancer (PCa) remains as one of the most controversial issues in health care because of the dilemmas related to screening using Prostate Specific Antigen (PSA). A high number of false positive biopsies and an elevated rate of overdiagnosis are the main problems associated with PSA. New PCa biomarkers have been recently proposed to increase the predictive value of PSA. The published results showed that PCA3 score, Prostate Health Index and 4Kscore can reduce the number of unnecessary biopsies, outperforming better than PSA and the percentage of free PSA. Furthermore, 4Kscore provides with high accuracy an individual risk for high-grade PCa. High values of PHI are also associated with tumor aggressiveness. In contrast, the relationship of PCA3 score with aggressiveness remains controversial, with studies showing opposite conclusions. Finally, the development of molecular biology has opened the study of genes, among them TMPRSS2:ERG fusion gene and miRNAs, in PCa detection and prognosis.

Wang S, Zhang Q, Xu D, et al.
Characterize the difference between TMPRSS2-ERG and non-TMPRSS2-ERG fusion patients by clinical and biological characteristics in prostate cancer.
Gene. 2018; 679:186-194 [PubMed] Related Publications
The TMPRSS2-ERG gene fusion were frequently found in prostate cancer, and thought to play some fundamental mechanisms for the development of prostate cancer. However, until now, the clinical and prognostic significance of TMPRSS2-ERG gene fusion was not fully understood. In this study, based on the 281 prostate cancers that constructed from a historical watchful waiting cohort, the statistically significant associations between TMPRSS2-ERG gene fusion and clinicopathologic characteristics were identified. In addition, the Elastic Net algorithm was used to predict the patients with TMPRSS2-ERG fusion status, and good predictive results were obtained, indicating that this algorithm was suitable to this prediction problem. The differential gene network was constructed from the network, and the KEGG enrichment analysis demonstrated that the module genes were significantly enriched in several important pathways.

Vicentini C, Cantù C, Antonello D, et al.
ERG alterations and mTOR pathway activation in primary prostate carcinomas developing castration-resistance.
Pathol Res Pract. 2018; 214(10):1675-1680 [PubMed] Related Publications
INTRODUCTION: One of the most common sites of distant metastasization of prostate cancer is bone, but to date reliable biomarkers able to predict the risk and timing of bone metastasization are still lacking.
PATIENTS AND METHODS: Surgically resected paraffin embedded samples from 12 primary prostate cancers that developed metachronous bone metastasis at different time points were studied (six cases within 2 years, six cases after 5 years from surgery). A targeted next-generation DNA and RNA sequencing able to assess simultaneously mutations, copy number alterations and fusion events of multiple genes was used. Immunohistochemistry was used to assess mTOR pathway activation.
RESULTS: Rearrangements of ETS family genes, molecular alterations in PTEN and TP53 genes were detected in 10, 6 and 5 cancers, respectively. Nine samples showed TMPRSS2-ERG fusions, which were associated with increased ERG expression at immunohistochemistry. mTOR pathway activation was documented in 6 patients, with a clear trend of prevalence in late-metastatic patients (p = 0.08).
CONCLUSIONS: A simultaneous next-generation targeted DNA and RNA sequencing is applicable on routine formalin-fixed paraffin-embedded tissues to assess the multigene molecular asset of individual prostate cancers. This approach, coupled with immunohistochemistry for ERG and mTOR pathway proteins, may help to better characterize prostate cancer molecular features with a potential impact on clinical decisions.

Ahearn TU, Peisch S, Pettersson A, et al.
Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease.
Carcinogenesis. 2018; 39(12):1431-1437 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Frank S, Nelson P, Vasioukhin V
Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects.
F1000Res. 2018; 7 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Prostate cancer (PCa) is a disease of mutated and misregulated genes. However, primary prostate tumors have relatively few mutations, and only three genes (

Fujita K, Nonomura N
Urinary biomarkers of prostate cancer.
Int J Urol. 2018; 25(9):770-779 [PubMed] Related Publications
The development of more specific biomarkers for prostate cancer and/or high-risk prostate cancer is necessary, because the prostate-specific antigen test lacks specificity for the detection of prostate cancer and can lead to unnecessary prostate biopsies. Urine is a promising source for the development of new biomarkers of prostate cancer. Biomarkers derived from prostate cancer cells are released into prostatic fluids and then into urine. Urine after manipulation of the prostate is enriched with prostate cancer biomarkers, which include prostate cancer cells, DNAs, RNAs, proteins and other small molecules. The urinary prostate cancer antigen 3 test is the first Food and Drug Administration-approved RNA-based urinary marker, and it helps in the detection of prostate cancer on repeat biopsy. The SelectMDx test is based on messenger RNA detection of DLX1 and HOXC6 in urine after prostate massage, and helps in the detection of high-risk prostate cancer on prostate biopsy. Exosomes are extracellular vesicles with a diameter of 30-200 nm that are secreted from various types of cells. Urinary prostate cancer-derived exosomes also contain RNAs and proteins specific for prostate cancer (e.g. PCA3 and TMPRSS2-ERG), and could be promising sources of novel biomarker discovery. The ExoDx Prostate test is a commercially available test based on the detection of three genes (PCA3, ERG and SPDEF) in urinary exosomes. Advancement of comprehensive analysis (microarray, mass spectrometry and next-generation sequencing) has resulted in the discovery of several urinary biomarkers. Non-invasive urinary markers can help in the decision to carry out prostate biopsy or in the design of a therapeutic strategy.

Sandoval GJ, Pulice JL, Pakula H, et al.
Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis.
Mol Cell. 2018; 71(4):554-566.e7 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.

Koide H, Kimura T, Inaba H, et al.
Comparison of ERG and SPINK1 expression among incidental and metastatic prostate cancer in Japanese men.
Prostate. 2019; 79(1):3-8 [PubMed] Related Publications
BACKGROUND: TMPRSS2:ERG fusion is the most common genetic event in prostate cancer (PCa). However, its association with prognosis is controversial. Overexpression of serine protease inhibitor Kazal-type 1 (SPINK1) was almost exclusively defined in ERG-negative PCa in most studies. This study aimed to determine the association between ERG and SPINK1 expression and the biological aggressiveness of PCa by analyzing their expression in incidental and metastatic cohorts.
METHODS: A total of 143 cystoprostatectomy specimens of invasive bladder cancer and 98 biopsy specimens from de novo metastatic PCa were analyzed. The prostate gland of cystoprostatectomy specimens was fixed and sliced in step sections. Immunohistochemistry of ERG and SPINK1 was conducted, and the results were correlated with the clinicopathological characteristics of the patients.
RESULTS: The overall prevalence of incidental cancer was 32.2% (46/143). The frequencies of both ERG and SPINK1 expression were not significantly different between incidental and metastatic cohorts (15.2% and 14.3%; P = 1.00, and 6.5% and 12.2%; P = 0.38, respectively). In the metastatic cohort, any pre-treatment factors were not significantly associated with the frequencies of ERG and SPINK1 expression. However, SPINK1 expression was significantly associated with a shorter time to castration-resistant PCa (CRPC) (P = 0.048). Meanwhile, overall survival was not significantly associated with the expression status of ERG and SPINK1 (P = 0.71).
CONCLUSIONS: ERG and SPINK1 expression may not have significant influence on the metastatic behavior of PCa. SPINK1 expression was significantly associated with a shorter time to CRPC in metastatic PCa. The expression profile of ERG and SPINK1 may be a useful predictor for effect of androgen deprivation therapy in patients with metastatic castration-sensitive PCa.

Shan L, Ji T, Su X, et al.
TMPRSS2-ERG Fusion Promotes Recruitment of Regulatory T cells and Tumor Growth in Prostate Cancer.
Am J Med Sci. 2018; 356(1):72-78 [PubMed] Related Publications
BACKGROUND: This study was designed to examine the effect of transmembrane protease serine 2 ETS-related gene (TMPRSS2-ERG) fusion on regulatory T cells and tumor growth in prostate cancer, which may provide a new potential therapeutic direction for PCa.
METHODS: The effect of TMPRSS2-ERG fusion on the migration of Treg cells and tumor growth in a mouse model was investigated in vitro and in vivo. TMPRSS2-ERG fusion in biopsy tissues was performed by fluorescence in situ hybridization and the expression of ERG and Forkhead box P3 was detected by gel electrophoresis, real-time quantitative reverse transcription polymerase chain reaction and Western blot. Enzyme-linked immunosorbent assay and flow cytometry were used to analyze transforming growth factor β levels and the number of regulatory T cells, respectively. Finally, the infiltration of regulatory T cells was analyzed by Forkhead box P3 immunohistochemistry.
RESULTS: Fluorescence in situ hybridization analysis showed that the TMPRSS2-ERG fusion gene was positive in prostate cancer and that the messenger RNA and protein expression of ERG were significantly up-regulated in prostate cancer biopsy tissues. Furthermore, the number of regulatory T cells and the levels of Forkhead box P3 and transforming growth factor β were significantly increased in prostate cancer. TMPRSS2-ERG fusion increased the migration and activation of regulatory T cells in vitro and promoted subcutaneous tumor size and regulatory T cells infiltration in mouse models.
CONCLUSIONS: TMPRSS2-ERG fusion can regulate the recruitment and infiltration of regulatory T cells to promote tumor growth in prostate cancer.

Xu Z, Wang Y, Xiao ZG, et al.
Nuclear receptor ERRα and transcription factor ERG form a reciprocal loop in the regulation of TMPRSS2:ERG fusion gene in prostate cancer.
Oncogene. 2018; 37(48):6259-6274 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
The TMPRSS2:ERG (T:E) fusion gene is generally believed to be mainly regulated by the activated androgen receptor (AR) signaling in androgen-dependent prostate cancer. However, its persistent expression in castration-resistant and neuroendocrine prostate cancers implies that other transcription factors might also regulate its expression. Here, we showed that up-regulation of nuclear receptor estrogen-related receptor alpha (ERRα) was closely associated with the oncogenic transcription factor ERG expression in prostate cancer, and their increased coexpression patterns were closely associated with high Gleason scores and metastasis in patients. Both ERRα and ERG exhibited a positive expression correlation in a castration-resistant prostate cancer (CRPC) xenograft model VCaP-CRPC. We showed that ERRα could directly transactivate T:E fusion gene in both AR-positive and -negative prostate cancer cells via both ERR-binding element- and AR-binding element-dependent manners. Ectopic T:E expression under ERRα regulation could promote both in vitro invasion and in vivo metastasis capacities of AR-negative prostatic cells. Intriguingly, ERG expressed by the T:E fusion could also transactivate the ERRα (ESRRA) gene. Hereby, ERRα and ERG can synergistically regulate each other and form a reciprocal regulatory loop to promote the advanced growth of prostate cancer. Inhibition of ERRα activity by ERRα inverse agonist could suppress T:E expression in prostate cancer cells, implicating that targeting ERRα could be a potential therapeutic strategy for treating the aggressive T:E-positive prostate cancer.

Gerashchenko GV, Mevs LV, Chashchina LI, et al.
Expression of steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion.
Exp Oncol. 2018; 40(2):101-108 [PubMed] Related Publications
AIM: To analyze an expression pattern of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion; and to examine a putative correlation between gene expression and clinical characteristics, to define the molecular subtypes of prostate cancer.
MATERIALS AND METHODS: The relative gene expression (RE) of 33 transcripts (27 genes) and the presence/absence of the TMPRSS2/ERG fusion were analyzed by a quantitative PCR. 37 prostate cancer tissues (T) paired with conventionally normal prostate tissue (CNT) and 21 samples of prostate adenomas were investigated. RE changes were calculated, using different protocols of statistics.
RESULTS: We demonstrated differences in RE of seven genes between tumors and CNT, as was calculated, using the 2-ΔCT model and the Wilcoxon matched paired test. Five genes (ESR1, KRT18, MKI67, MMP9, PCA3) showed altered expression in adenocarcinomas, in which the TMPRSS2/ERG fusion was detected. Two genes (INSR, isoform B and HOTAIR) expressed differently in tumors without fusion. Comparison of the gene expression pattern in adenomas, CNT and adenocarcinomas demonstrated that in adenocarcinomas, bearing the TMPRSS2/ERG fusion, genes KRT18, PCA3, and SCHLAP1 expressed differently. At the same time, we detected differences in RE of AR (isoform 2), MMP9, PRLR and HOTAIR in adenocarcinomas without the TMPRSS2/ERG fusion. Two genes (ESR1 and SRD5A2) showed differences in RE in both adenocarcinoma groups. Fourteen genes, namely AR (isoforms 1 and 2), CDH1, OCLN, NKX3-1, XIAP, GCR (ins AG), INSR (isoform A), IGF1R, IGF1R tr, PRLR, PRL, VDR and SRD5A2 showed correlation between RE and tumor stage. RE of four genes (CDH2, ESR2, VDR and SRD5A2) correlated with differentiation status of tumors (Gleason score). Using the K-means clustering, we could cluster adenocarcinomas in three groups, according to gene expression profiles. A specific subtype of prostate tumors is characterized by the activated ERG signaling, due to the presence of TMPRSS2/ERG fusion, and also by high levels of the androgen receptor, prolactin, IGF, INSR and PCA3.
CONCLUSIONS: We have found the specific differences in expression of the steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes, depending on the pre-sence/absence of the TMPRSS2/ERG fusion in prostate adenocarcinomas, CNT and adenomas. We showed three different gene expression profiles of prostate adenocarcinomas. One of them is characteristic for adenocarcinomas with the TMPRSS2/ERG fusion. Further experiments are needed to confirm these data in a larger cohort of patients.

Lee SR, Choi YD, Cho NH
Association between pathologic factors and ERG expression in prostate cancer: finding pivotal networking.
J Cancer Res Clin Oncol. 2018; 144(9):1665-1683 [PubMed] Related Publications
PURPOSE: To evaluate associations between pathologic factors and erythroblast transformation-specific (ETS)-related gene (ERG) expression in prostate cancer patients. Using next-generation sequencing, we identified target genes and regulatory networks.
METHODS: ERG expression in 60 radical prostatectomies was compared with pathological findings by association rule mining with the Apriori algorithm. Whole-exome and RNA sequencing were performed on three formalin-fixed, paraffin-embedded ERG-positive and negative prostate cancer samples. A network diagram identifying dominant altered genes was constructed using Cytoscape open-source bioinformatics platform and GeneMania plugin.
RESULTS: Pathologic conditions positive for perineural invasion, apical margins, and Gleason score 3 + 4 = 7 were significantly more likely to be ERG-positive than other pathologic conditions (p = 0.0008), suggesting an association between ERG positivity, perineural invasion, apical margins, and Gleason score 3 + 4 = 7 (Firth's logistic regression: OR 42.565, 95% CI 1.670-1084.847, p = 0.0232). Results of whole-exome and RNA sequencing identified 97 somatic mutations containing common mutated genes. Regulatory network analysis identified NOTCH1, MEF2C, STAT3, LCK, CACNA2D3, PCSK7, MEF2A, PDZD2, TAB1, and ASGR1 as pivotal genes. NOTCH1 appears to function as a hub, because it had the highest node degree and betweenness. NOTCH1 staining was found 8 of 60 specimens (13%), with a significant association between ERG and NOTCH1 positivity (p = 0.001).
CONCLUSIONS: Evaluating the association between ERG expression and pathologic factors, and identifying the regulatory network and pivotal hub may help to understand the clinical significance of ERG-positive prostate cancer.

Pakula H, Linn DE, Schmidt DR, et al.
Protocols for Studies on TMPRSS2/ERG in Prostate Cancer.
Methods Mol Biol. 2018; 1786:131-151 [PubMed] Related Publications
TMPRSS2/ERG is the most common type of gene fusions found in human prostate cancer. There are two important features of TMPRSS2/ERG fusions. One is that these gene fusions lead to ectopic expression of ERG, an ETS family transcription factor, in prostate epithelial cells from the 5' control region of an androgen/estrogen dual-responsive gene, TMPRSS2; the other is that ~60% of these fusions are generated via intrachromosomal deletion of the interstitial region between TMPRSS2 and ERG. To recapitulate these important aspects of TMPRSS2/ERG fusions, we generated several TMPRSS2/ERG knockin mouse models based on the endogenous Tmprss2 locus. We found that TMPRSS2/ERG represents an early event in prostate tumorigenesis, by sensitizing prostate cells for cooperation with other oncogenic events, such as PTEN-deficiency. We also found that the interstitial region between TMPRSS2 and ERG harbors at least one prostate tumor suppressor, ETS2, whose loss contributes to prostate cancer progression. In this protocol, we describe how these knockin mouse models can be utilized to study roles of TMPRSS2/ERG fusions in prostate cancer development both in vivo and in vitro.

Knuuttila M, Mehmood A, Mäki-Jouppila J, et al.
Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer.
Endocr Relat Cancer. 2018; 25(9):807-819 [PubMed] Related Publications
Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate (

Massaad-Massade L, Boutary S, Caillaud M, et al.
New Formulation for the Delivery of Oligonucleotides Using "Clickable" siRNA-Polyisoprenoid-Conjugated Nanoparticles: Application to Cancers Harboring Fusion Oncogenes.
Bioconjug Chem. 2018; 29(6):1961-1972 [PubMed] Related Publications
The aim of the present study is to take advantage of the unique property of polyisoprenoid chains to adopt a compact molecular conformation and to use these natural and biocompatible lipids as nanocarriers of drugs to deliver siRNA. A new chemical strategy is applied here to conjugate squalene (SQ) and solanesol (SOLA) to siRNA consisting of an activated variant of the azide-alkyne Huisgen cycloaddition also known as copper-free (Cu-free) click chemistry. We conjugated siRNA against TMPRSS2-ERG, a fusion oncogene found in more than 50% of prostate cancers to SQ or SOLA. First, several parameters such as molar ratio, solvents, temperature, incubation time, and the annealing schedule between both siRNA strands were investigated to bioconjugate the SQ or SOLA via Cu-free click chemistry. The best parameters of the new bioconjugation approach allowed us to (i) increase the synthesis yield up to 95%, (ii) avoid the formation of byproducts during the synthesis, and (iii) improve the reproducibility of the bioconjugation. Then, the biological activity of the resulting nanoparticles was assessed. In vitro, all four formulations were able to decrease the corresponding oncogene and oncoprotein expression. In vivo, only two of the four nanoformulations showed anti-neoplastic activity that seems to be tightly related to their dissimilar biodistribution behavior. In conclusion, we performed a new approach easily transposable for pharmaceutical development to synthesize siRNA-SQ and siRNA-SOLA and to obtain efficient siRNA-nanoparticles. The robustness of the process could be extended to several other polyterpenes and likely applied to other siRNA targeting genes whose overexpression results in the development of cancers or other genetic diseases.

Mohamed AA, Xavier CP, Sukumar G, et al.
Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth.
Cancer Res. 2018; 78(13):3659-3671 [PubMed] Related Publications
Oncogenic activation of the ETS-related gene (

Nordstrand A, Bovinder Ylitalo E, Thysell E, et al.
Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity.
Int J Mol Sci. 2018; 19(4) [PubMed] Article available free on PMC after 31/12/2019 Related Publications
Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naïve (

Feiersinger GE, Trattnig K, Leitner PD, et al.
Olaparib is effective in combination with, and as maintenance therapy after, first-line endocrine therapy in prostate cancer cells.
Mol Oncol. 2018; 12(4):561-576 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first-line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion-positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first-line endocrine therapy for PCa patients with diagnosed BRCAness.

Singhal U, Wang Y, Henderson J, et al.
Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature.
Mol Cancer Res. 2018; 16(4):643-654 [PubMed] Article available free on PMC after 31/12/2019 Related Publications
The trend toward precision-based therapeutic approaches dictated by molecular alterations offers substantial promise for men with metastatic castration-resistant prostate cancer (mCRPC). However, current approaches for molecular characterization are primarily tissue based, necessitating serial biopsies to understand changes over time and are limited by the challenges inherent to extracting genomic material from predominantly bone metastases. Therefore, a circulating tumor cell (CTC)-based assay was developed to determine gene expression across a panel of clinically relevant and potentially actionable prostate cancer-related genes. CTCs were isolated from the whole blood of mCRPC patients (

Hinsch A, Brolund M, Hube-Magg C, et al.
Immunohistochemically detected IDH1
World J Urol. 2018; 36(6):877-882 [PubMed] Related Publications
BACKGROUND: IDH1 mutations are oncogenic through induction of DNA damage and genome instability. They are of therapeutic interest because they confer increased sensitivity to radiation and cytotoxic therapy and hold potential for vaccination therapy.
METHODS: In this study, we analyzed more than 17,000 primary prostate cancer tissues with a mutation-specific antibody for the IDH1
RESULTS: IDH1 mutation-specific staining was found in 42 of 15,531 (0.3%) interpretable cancers. IDH1 mutation was associated with higher preoperative PSA and Gleason grade (p < 0.05, each) but was unrelated to PSA recurrence. A comparison with other molecular tumor features available from earlier studies revealed that TMPRSS2-ERG fusion as well as deletion of PTEN, 5q21, 6q15, and 3p13 was less frequent in IDH1-mutated than in non-mutated cancer. Increased lethality of genetically instable, "aberration-rich" cancer cells in the presence of IDH1 mutations could possibly explain this observation. Heterogeneity analysis revealed a homogeneous mutation in only 1 of 16 IDH1-mutated cancers. This high degree of heterogeneity may profoundly limit therapeutic targeting of IDH1 mutations in prostate cancer.
CONCLUSIONS: The data show that 0.3% of prostate cancers have an IDH1

Antonelli A, Palumbo C, Veccia A, et al.
Biological effect of neoadjuvant androgen-deprivation therapy assessed on specimens from radical prostatectomy: a systematic review.
Minerva Urol Nefrol. 2018; 70(4):370-379 [PubMed] Related Publications
INTRODUCTION: Androgen-deprivation therapy (ADT) administered in neoadjuvant setting before radical prostatectomy (RP) represents an ideal in vivo human model to test the efficacy of hormonal treatments in prostate cancer (PCa). This review summarizes the findings from published studies specifically focused on the biological effects of ADT assessed on specimens from RP. The aim is to provide a base of knowledge that might be used to design future studies on neoadjuvant therapy for PCa.
EVIDENCE ACQUISITION: A systematic review of the literature was performed according to the PRISMA statements. Search protocol identified published studies including a detailed analysis on specimen from RP to assess the biological effects of neoadjuvant ADT. In November 2017, Medline, Embase, and Scopus databases were searched using the terms "neoadjuvant" AND ("hormone therapy" OR "androgen deprivation therapy") AND "prostate cancer" in the "Title/Abstract" fields. Effects of ADT were classified according to four pathways - suppression of cellular proliferation, induction of apoptosis, alteration of immune response and onset of hormonal refractoriness - and relative markers of response were identified.
EVIDENCE SYNTHESIS: From 1856 papers initially retrieved, 19 studies were finally selected and included into the present review. ADT was constituted by luteinizing hormone-releasing hormone (LH-RH) agonist alone in two, peripheral anti-androgen alone in one, both in 10, abiraterone acetate in one, unspecified in five. According to the above-mentioned four pathways, the following markers of response were identified: transcription of the oncogene TMPRSS2:ERG, translation of Aurora-A, coding of β1C integrin gene, translation of Ki-67, expression of nerve growth factors TrkA and p75NGFR, anti-angiogenic activity and micro-vessel density were involved into suppression of proliferation; mRNA transcription of bcl-2, expression of cleaved caspase-3 and translation of insulin growth factor binding protein 3, into induction of apoptosis; expression of IL-7 gene, programmed death-ligand 1, and increase of intra-prostatic T-cell population were related to alteration of immune response; finally, expression of heat shock protein 27 and de-differentiation of PCa to neuroendocrine cells, influenced the onset of hormonal refractoriness.
CONCLUSIONS: Despite a potential high interest, unexpectedly, only 19 heterogeneous studies investigated the effects of ADT through the analysis of specimens from RP. The present review summarizes the available evidences on this topic showing that ADT interferes on PCa at different levels that can be investigated by specific biological markers.

Koukourakis MI, Kakouratos C, Kalamida D, et al.
Comparison of the effect of the antiandrogen apalutamide (ARN-509) versus bicalutamide on the androgen receptor pathway in prostate cancer cell lines.
Anticancer Drugs. 2018; 29(4):323-333 [PubMed] Related Publications
Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D) and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3, carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and phosphorylated AR and by increasing the levels of prostate-specific antigen and TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent by bicalutamide at 10 μmol/l, both in normoxia and in hypoxia. ARN had a stronger antiproliferative effect than bicalutamide, which was prominent in the 22Rv1 hormone-responsive cell line, and completely repressed cell proliferation at a concentration of 100 μmol/l. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was noted. The PC3 and DU145 cell lines showed poor expression of the proteins and were not responsive to testosterone. On the basis of in-vitro studies, evidence has been reported that ARN is more potent than bicalutamide in blocking the AR pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent, repressive effect on cell proliferation.

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