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Cancer Biology & Therapy Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kcbt20 The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy Kuo-Cheng Huanga, Mohammed Alshalalfab, Samar A Hegazyabc, Michael Dolpha, Bryan Donnellydb & Tarek A Bismaraefb a Department of Pathology and Laboratory Medicine; University of Calgary and Calgary Laboratory Services; Calgary, AB Canada b The Prostate Cancer Center; Calgary, AB Canada c Department of Pathology; Faculty of Medicine; Zagazig University; Zagazig, Egypt d Department of Urology; University of Calgary; Calgary, AB Canada Click for updates e Departments of Oncology, Biochemistry and Molecular Biology; Calgary, AB Canada f Southern Alberta Cancer Institute and Tom Baker Cancer Center; Calgary, AB Canada Published online: 27 Jun 2014.

To cite this article: Kuo-Cheng Huang, Mohammed Alshalalfa, Samar A Hegazy, Michael Dolph, Bryan Donnelly & Tarek A Bismar (2014) The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy, Cancer Biology & Therapy, 15:9, 1120-1128, DOI: 10.4161/cbt.29689 To link to this article: http://dx.doi.org/10.4161/cbt.29689

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ic TMPRSS2 C a 1 li partment of Pathology and Medicine; Laboratory D The prognostic significance of combined ERG combined of significance prognostic The l A n e was used for validation and characterization of potential gene signatures associated with ERG and and ERG with associated signatures gene potential of characterization and validation for used was cohort Swedish watchful-waiting The parameters. clinical-pathological various with correlated was status expression A (T prostate the of resection and ERG and ERG combined of value prognostic the deregulated in PCa. deregulated (PCSM) compared with patients with ERG-negative/ with patients with (PCSM) compared genetic alteration likely responsible for disease progression. The prognostic value of combined ERG/ combined of value prognostic The progression. disease for responsible likely alteration genetic and multivariate analysis (HR: 2; 95% (HR: analysis CI: 0.97–4.1, multivariate and ERG/ score. Gleason P=0.057), included which 95% 3.3; (HR: CI: 1.9–5.6, univariate in 4.25E P= cohort waiting Swedish watchful the in validated was to PCSM ( subgroup CRPC the included which cohort overall the in attenuated was status characterized 152 W including signatures characterized genes status cancer progression. cancer prostate in targets therapeutic and prognostic as potential investigated further be should genes associated its and S ic B Canada; d a t l vPCa) vs. those with castrate-resistant PCa (CRPC) undergoing channel T channel undergoing (CRPC) PCa castrate-resistant with those vPCa) vs. udy Keywords: S ERG and androgen receptor ( receptor androgen and ERG In conclusion, combined ERG/ combined conclusion, In Patients with combined ERG-positive/ combined with Patients in patients with prostate cancer managed t udy (21q22.3) and other members of the ETS of the (21q22.3) members other and 3 partment of Pathology; Faculty of Medicine; Zagazig Zagazig Medicine; of Faculty Pathology; of partment D A e R p 1 and androgen receptor expression receptor androgen and , Mohammed Mohammed , rotein expression by immunohistochemistry in a cohort of 312 of by transurethral acohort in diagnosed PCa with men by immunohistochemistry expression rotein ERG protein expression, immunohistochemistry, Gleason score, tumor volume,hormone therapy, tumor score, Gleason immunohistochemistry, ERG protein expression, by androgen deprivation therapyby androgen Introduction 1-5 To date, it is suggested that ERG that To it suggested is date, U A R P). Patients were divided into those with no prior hormonal treatment (designated as (designated PCa/ treatment hormonal prior no with into those P). divided were Patients lshalalfa A A R R o ) are known to function cooperatively in prostate cancer (PCa) progression. However, (PCa) progression. cancer prostate in cooperatively to function known ) are ERG verexpression signifies a class of patients at highest-risk of PCSM with specific key specific with PCSM of at highest-risk patients aclassof signifies verexpression 2 U , Samar n A - gene rearrange iversity of and Calgary Services; Laboratory Calgary Calgary, A R hi R e (21q22.2). gh expression profile demonstrated higher rates of PCa-specific mortality mortality PCa-specific of rates higher demonstrated profile expression gh xpression and potential pathways are not well characterized. We assessed We assessed characterized. well not pathways are potential and xpression cancer specific mortality specific cancer C A ancer Biology& Therapy Hegazy A A Cancer Biology& Therapy 15:9,1120–1128;September2014;©2014LandesBioscience B C fam R l U n anada; anada; ow in patients with no prior treatment ( treatment prior no with ow patients in iversity; Zagazig, Egypt; Egypt; Zagazig, iversity; N is is T - - , PI3K/ 1,2,3 6 Southern Southern rearrangement. to ERG surrogate as documented been has histochemistry mRNA levels. increased and protein expression AR this, with keeping in and, reactivation AR is to CRPC progression driving in mediators key one of the that demonstrated have investigations Recent CRPC. lethal and into aggressive progression by disease followed usually is this regression, tumor temporary causing treatment effective value. or no prognostic little with it where associate cohorts, surgical with compared cohorts waiting) watchful and (i.e., expectant non-surgical in outcome mainly clinical adverse with associated ease progression. ease , Michael The androgen receptor (AR) is a known key mediator of dis mediator key aknown is (AR) receptor androgen The A K 6-14 T and chemokine signaling pathways known to be to be pathways known signaling chemokine T and A l

berta Cancer Institute and Tom Baker Cancer Center; Calgary, Calgary, Center; Cancer Tom and Baker Institute Cancer berta Recently, ERG protein expression assessed by immuno assessed Recently, ERG protein expression D = 0.096). The prognostic significance n =125, significance prognostic P=0.096). The ol 4 partment of D 18-23 e ph U 15,16 R 17 1 P to relieve obstructive symptoms. The The symptoms. obstructive P to relieve nnelly Bryan , Although androgen ablation is initially very very initially is ablation androgen Although U D r ology; A o B Canada; U = 90, P=0.032),n =90, this but n iversity of Calgary, Calgary; 2,4 A 2 The Prostate Cancer Center; Center; Cancer Prostate The R , and Tarek A A . R o R overexpression overexpression verexpression verexpression

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©2014 Landes Bioscience. Do not distribute. Downloaded by [University of Alberta] at 13:03 29 January 2015 www.landesbioscience.com and are responsible in part for the occurrence of CRPC. occurrence for the part in responsible are and undergoing channel TURP to relieve obstructive symptoms. obstructive to relieve TURP channel undergoing hormone) agonist, hormone-releasing (luteinizing by LH-RH treated patients CRPC advanced locally and PCa/AdvPCa) as (designated (TURP) of prostate resection by transurethral nosed diag patients PCa advanced of locally consisting cohort surgical anon- in protein expression ERG/AR of combined significance prognostic the study, we investigated this oneIn either alone. of analysis than relevant clinically and more be biologically may of ERG status expression of the assessment bined interacting signaling pathways. signaling interacting tightly of several to perturbation leading alterations tiple genetic AR to promote invasion. tumor AR but ERG activity, of AR regulation the under for ERG experimentally demonstrated been has action AR of tumor progression, tumor of of ERG either lation distribution. ( group sub PCa/AdvPCa the vs. subgroup CRPC the in positivity of ERG frequency higher toward significance amarginal was volume. There tumor and GS to PCSM, relation in patients of subgroups two the between difference significant was There analyzed. subgroups of the demographics patient onstrates prostatectomy. radical received had cohort the in None patients respectively. of the assessment, AR for ERG and 292/312 and (93.5%) (95.8%) patient’s were available samples of 299/312 Atotal PCa/AdvPCa). as (designated therapy monal (193/312 patients ofder the no prior [61.86%]) hor received remain the and CRPC) as (designated therapy prior hormonal (119/312 cohort overall the [38.14%]) received had of patients of Asubgroup recorded. are mortalities specific cancer and overall as well as TURP) (channel obstruction symptomatic to relieve intervention or surgical therapy of hormonal of time terms in progression to disease 1.5–100.2 regards in Data mo). 50.7–93.5 of follow-up 23.45 time average y) with mo (range ties may be required in treating CRPC. treating in required be may ties modali therapeutic combined that suggesting regression, tumor greater achieves pathways signaling PI3K AR and both inhibiting in PCa progression. PCa in interact multiple genes between cooperation selective and bations that target just one of these signaling pathways. signaling one just of these target that treatments in resistance to therapeutic rise giving tion, thereby inhibi of feedback relief due to other the of the to activation leads pathways signaling PI3K of the either or AR inhibition tive selec pathway. Furthermore, PI3K the signaling in of alterations instance, Mean patients’ age for the overall cohort was 76.5 was cohort y(range overall for the age patients’ Mean population Study Based on this tight interaction, we hypothesized that com that we hypothesized interaction, tight on this Based The development of CRPC, involves accumulation of mul accumulation involves developmentThe of CRPC, , , and PTEN , and ERG P = 0.057). No difference was noted in AR expression expression AR noted in was =0.057). No difference PTEN loss has been associated with increased frequency frequency increased with associated been has loss or AR or 28 genomic aberrations interplay in PCa PCa in interplay aberrations genomic suggesting that multiple genetic pertur

alone is not sufficient for promotion not is sufficient alone Results 1,27 17 For example, it is known that that it known is For example, It is documented that upregu that It documented is 25 Similar reciprocal inter reciprocal Similar can in turn regulate regulate turn in can and AR and 25,26 Table In support, support, In C which is is which ancer Biology& Therapy

in PCa PCa in 1 dem 24 For For ------non-significant trend toward higher-rate of PCSM compared compared of higher-rate PCSM toward trend non-significant showed high ERG-positive/AR exhibiting tumors with patients cohort, total the within contrast, In cohort. study ofgroup the sub or any overall the either in of higher-rate PCSM with ciated asso significantly was by itself expression Neither ERG nor AR (10.2% 47.8%) subgroups vs. CRPC ( and AdvPCa PCa/ the between existed difference asignificant noted above, progression disease and survival overall mortality, specific cancer prostate to tion [48.1%]) ( 38/79 vs. (25/41 [61.0%] association such not demonstrate did subgroup -negative cases, respectively ( and ERG-positive in expression AR high exhibited cores TMA (39.5%) 149/293 vs. 34/86 where ofgroup patients, (50.9%) of sub PCa/AdvPCa the in marginal was 0.143). association This ( respectively cores, TMA ERG-negative and ERG-positive in expression 231/429vs. AR (53.9%) high showed of cores 59/127 (46.5%) Specifically, cohort. patients overall the in PCa -negative and ERG-positive between expression AR high with of cases proportion the in no difference was there expression, sample core (TMA) microarray tissue on individual rately. Based sepa subgroups two the in AR of ERG and significance nostic prog the to investigate we sought activity, and/or expression AR ERG and in alteration treatment-mediated possible and cohorts cancer prostate resistant tration and moderate intensity combined. PCSM, prostate cancer specific mortality. specific cancer prostate PCSM, combined. intensity moderate and * Patients’ demographics in the PCa and CRPC subgroups CRPC and PCa the in demographics Table 1. Patients’ N o A total of 57/304 (18.7%) of patients experienced PCSM. As As of (18.7%)57/304 PCSM. A total experienced of patients rela in status expression protein AR and ERG Combined characteristics clinical-pathologic the in to differences Due cas and incidental/advanced the in expression AR and ERG t all cases have available information. Low Low information. have available cases t all N oiie5 2.% 23(34.3%) 53(22.8%) Positive = 5 49(28.0%) =<5% Volume 43 5(.% 4(100%) 15(6.3%) 31(13.1%) 7 (4+3) 7 (3+4) gtv 7 7.% 44(65.7%) 179(77.2%) egative PCSM ih17(20)34(50.7%) 117(52.0%) High 5 2 7.% 46(100%) 126(72.0%) >5% Low ERG Y N >7 <7 AR GS 7 es

1 8.% 36(52.2%) 211(89.8%) o C/dPaCRPC PCa/AdvPCa 0 4.% 33(49.3%) 108 (48.0%) 4(02)3 4.% <0.001 33(47.8%) 24 (10.2%) 2(88)64(92.8%) <0.001 92 (38.8%) 1(1.4%) 99 (41.8%) 6(94)4(5.8%) 46 (19.4%) = 0.186). P = = 0.065). In contrast, the CRPC CRPC the P = 0.065). contrast, In 0 0 A R r efers to negative, weak, weak, tonegative, efers Pvalue P < 0.001 0.857 0.057 < 0.001). < 1121 P = ------

©2014 Landes Bioscience. Do not distribute. Downloaded by [University of Alberta] at 13:03 29 January 2015 ( ( (10/19 tumors [28.2%]) low AR 20/71 [52.6%]vs. ERG-negative/ with patients with compared survival overall worse significantly showed still tumors AR ERG-positive/high with subgroup, patients this in mortality overall the Assessing 1122 ( [8.4%]) low (5/19 6/71 vs. AR [26.3%] ERG-negative/ with compared subgroup PCa/AdvPCa the in more significant was PCSM and profile expression high AR ERG-positive/ between association The high. ERG-positive/AR 18.4%) 29.4% and 15.2%, vs. in (12.8%, AR; negative/low ERG- and AR ERG-negative/high AR, ERG-positive/low were tumors whose patients between comparable was PCSM [19.5%]) 18/92 vs. ( (10/33 [30.3%] low status ERG-negative/AR with patients with Fig. Figure 1. ing tumors compared with ERG-negative/ with compared tumors ing cancer specific mortality of PCa patients with ERG-positive/ with patients PCa of mortality specific cancer (i.e., no prior hormonal treatment) ( treatment) hormonal prior no (i.e., ERG-negative/ ERG-negative/

1C ). No significant difference in PCSM was noted in the the noted in was PCSM in difference No significant ). Kaplan–Meier survival curves. ( curves. survival Kaplan–Meier A R l ow expression in the PCa/ the in expression ow P = 0.096) ( =0.096) = 90, P=0.032).n =90, ( Fig. ) Kaplan–Meier survival curves to cancer specific mortality of PCa patients with ERG-positive/ with patients PCa of mortality specific to cancer curves survival A) Kaplan–Meier A R l

A ow expressing tumors in the overall study cohort ( cohort study overall the in tumors expressing ow 1A d vPCa patients group ( group patients vPCa P ). The incidence of of incidence The ). =0.032) ( C ) Kaplan–Meier survival curves to overall mortality of PCa patients with ERG-positive/ with patients PCa of mortality tooverall curves survival ) Kaplan–Meier A P R h C = 0.041) = Fig. ancer Biology& Therapy igh vs. ERG-negative/ vs. igh

1B = 0.041). P= n =90, ). ). data sets. We first defined 197 genes as ERG signature, 272 genes 272 genes 197 ERG signature, as genes defined We sets. first data cohort GSE8402 Swedish available publicly the we utilized PCa, status AR ( subgroup = 0.75) CRPC or in ( PCa/AdvPCa the either in expression AR ERG-negative/low with patients with compared patients) for PCa/AdvPCa therapy hormonal and patients for CRPC (i.e., TURP relief symptomatic for needed are treatments additional until time of the terms in progression disease in difference no significant had tumors (P (5/14 AR [35.7%] 12/21negative/low [57.1%], vs. respectively) ERG- and high ERG-positive/AR between subgroup CRPC =0.515). AR Moreover, ERG-positive/high with patients To define the molecular signature of ERG-positive/AR high high of ERG-positive/AR signature molecular To the define ERG-positive/high with associated of genes Identification A

R l ow expression in the subgroup of patients with PCa/ with patients of subgroup the in expression ow n =125, ( P=0.096). P = 0.29). = B ) Kaplan–Meier survival curves of of curves survival ) Kaplan–Meier A V R olume 15 Issue9 high express high A R h A d igh vs. vs. igh vPCa vPCa - P

©2014 Landes Bioscience. Do not distribute. Downloaded by [University of Alberta] at 13:03 29 January 2015 gression and the development of the CRPC. and gression pro to playamajor found rolePCa in been have amplification However, ( GS not it outperform did 0.62–1.27, CI: 95% 0.89; (HR: AR 0.78–2.45, 1.39; CI: 95% or P=0.254) ERG either (HR: with 0.97–4.1. CI: 95% P=0.057) 2; compared outcome (HR: cal clini the with correlation better showed and significant ginally higher-risk group of patients (not shown). of group patients higher-risk a defines AR of ERG and expression concomitant the that above data own our confirming status, AR or ERG-negative/high AR, ERG-positive/low AR, ERG-negative/low with tumors between 1.9–5.6, CI: 95% low. 3.3; HR: ERG-negative/AR with compared PCSM of athigher-risk were significantly samples AR positive/high low group. ERG- ERG-negative/AR the in 40/62 with pared outcome com lethal had AR ERG-positive/high with patients PCa 25/26 Specifically, disease. lethal outcome poor and with association significant documented which signature, high AR mortality specific prostate-cancer to relation in status AR positive/high pathways. signaling PI3K/AKT VEGF, and cycle, cell WNT, includes PCa high ERG-positive/AR the in deregulated pathways major biological The tumors. AR ERG-positive/high in turbed per are that pathways relevant biologically suggesting modules, functional interconnected into non-random grouped highly be www.landesbioscience.com Cytoscape mented in plug-in FI imple Reactome the using protein network tional Table in shown are involved pathways known and pattern, direction expression top 10 The their genes, signature. specific AR ERG-positive/high as were designated and status expression AR ERG+/high bined com to the were specific genes upregulated mostly fifty-two dred ( common in 9 genes only had signatures AR ERG The and signature. ERG/AR 270 and as signature, AR as ERG and AR, ERG and between experimentally demonstrated was interaction reciprocal PCa in none surgically treated patients. treated none in surgically PCa lethal with associated significantly are protein expression and tion. However, as previously documented, it is likely that ERG that it likely is documented, However,tion. previously as manipula to hormonal subjected not initially tumors in relevant more is markers combined two of the value prognostic the that suggest may which subgroup CRPC the including when uated atten was difference subgroup, this PCa/AdvPCa our in tumors AR ERG-negative/low with outcome compared clinical adverse progression. PCa In multivariable analysis, ERG-positive/AR high was still mar still was high ERG-positive/AR analysis, multivariable In ERG-positive/ our to validate cohort Swedish the We utilized ERG- combined of the value prognostic of the Validation The 152 signature genes were analyzed to construct afunc to construct 152The were analyzed genes signature Previous studies had shown that ERG that shown had studies Previous Although ERG-positive/AR high expression profile conferred conferred profile expression high ERG-positive/AR Although = 4.25E P = 1,27

2 suggesting that both cooperate functionally in in functionally cooperate both that suggesting . - 5 ( 29 Fig. (

Discussion Fig.

4 ). There was no prognostic difference difference no prognostic was There ).

3 ) which showed these genes to genes these showed ) which P = 0.528) alone. expression Table 12,13 30 gene rearrangements rearrangements gene

3 Moreover, astrong AR expression and and expression AR ). Fig.

2 ). One hun ). C ancer Biology& Therapy ------( modules functional interconnected highly non-random into grouped are genes these interactions, and function on known these genes, including WNT, including genes, these WNT pathways. WNT and ERG, AR the by targeting cells of PCa behavior aggressive of the attenuation documenting data in-vitro recent of the port sup further is combination expression ERG/AR other any in sion. progres for disease required are both that and progression PCa to enhance sufficient is alone overexpression neither ERG nor AR management. more aggressive require likely and gression pro of disease higher-risk with patients of PCa asubgroup nify sig profile expression high ERG-positive/AR with patients that it hypothesized is Therefore, noted above. rates mortality PCSM ( group sub each within of patients number limited of the reflective be may symptoms to relief therapy for additional requirement the until time of the terms in progression disease in differences any many have been found to interact with ERG and AR. Indeed, Indeed, AR. ERG and with to interact found been have many and progression of PCa stages various in implicated been ously ture genes specific to ERG-positive/AR high PCa ( PCa high to ERG-positive/AR specific genes ture 152 we defined signa subtype, molecular PCa aggressive of this mTOR, within the CRPC group. CRPC the within therapy prior hormonal by the altered are levels intensity AR and Fig. and ERG and Figure 2. with ERG or or ERG with genes were using identified ROC analysis; 152 genes were overlapped and ERG Experimental observation from recent reports suggest that that suggest reports recent from observation Experimental Finally, as a first step toward elucidating the mechanistic basis basis mechanistic the elucidating toward step afirst as Finally, 28

3 Our data documenting insignificant prognostic difference difference prognostic insignificant documenting data Our ), as most of the major biological pathways involved by pathways major biological of the most as ), = 52, 23, and 31) given the higher number of overall and and n = 52, of31) overall number 23, and higher the given 24,34

+ A high signature. Only 9 genes were in common between between common in were 9 genes Only signature. high / Venn diagram showing the intersection among the ERG, ERG, the among intersection the showing Venn diagram A R s R and chemokine and A ignatures. When combining the status of ERG and and ERG of status the combining When ignatures. R s ignatures. 31,32 15 Moreover, our inability to document to document Moreover, inability our 35 signaling pathways, have previ have pathways, signaling 32,33 VEGF, PTEN/PI3K/AKT/ VEGF, Fig.

3 ). Based Based ). A R , 270 1123 A R , ------

©2014 Landes Bioscience. Do not distribute. Downloaded by [University of Alberta] at 13:03 29 January 2015 1124 toERG/ related genes expressed TopTable 2. 10 differentially CDK2AP1 of a Overexpression signature. gene high ERG-positive/AR an CDK2P1 inhibitor aCDK2 encoding gene biology. Notably, cancer of the prostate found we have context the in studied been have genes identified some of only the far as intra- and extra-cellular signaling ( signaling extra-cellular and intra- as well as protein turnover specific regulation, tion, transcriptional differentia and growth cell cycle, cell including, processes lular of multiple cel to deregulation leads expression combined AR ERG and that suggest genes signature individual of the analysis cycle, EGF,cycle, PI3K signaling. and Wnt as pathway, such cell pathways in enriched are genes The interacting. highly are they as related ally Figure 3. EPM2 T C GPR S PSMB10 U D R

F SEC13 A D Gene U A BGCP3 K2 CM1L RG2 P Far upstream element (F BP1 B3B A A A P Gprotein-coupled receptor protein associated 1 sorting SP1 IP1 P1 Cyclin-dependent kinase 2associated Cyclin-dependent protein kinase 1 P1 Functional protein network of the 152 genes with enriched pathways. The 152 function The are genes pathways. 152 enriched the of with genes network protein Functional had been found in one study to lead to a reduction in in to areduction to lead one in study found been had D ev Tubulin, gamma complex associated protein 3 protein associated complex Tubulin, gamma S elopmentally regulated GTPbindingprotein 2 A EPM2 C1 suppr Proteasome subunit, betatype, 10 Member R Member A (Laforin) interacting protein 1 essor of actin mutations 1-Like essor ofactin Sec13 homolog Sec13 Description A S oncogene family Table U SE) bindingprotein to be upregulated as as upregulated to be

2 ). However, thus However, thus ). A C R ancer Biology& Therapy - - ERG-positive/AR highPCa Direction ofexpressionDirection in colorectal cancer. colorectal in chemotherapy to irinotecan resistance and carcinoma cellular hepato aggressive with associated been has of which expression 1), gene the Drg1 gene suppressor (differentiation-related tumor putative of the case the in illustrated is This models. xenograft mouse in and vitro in suppressors tumor as to function implicated been initially have that genes tumor-suppressors to overexpress cancers resistant therapeutically and aggressive mon for clinically However, not is clear. it study present not is uncom the in cancer prostate high ERG-positive/AR more aggressive the in ulated D D

U U U U U U U U ow ow p p p p p p p p n n 38 - G-protein mediated lysosomal degradation Synthesis ofPIPs at theERmembrane Protein andtight junctions transport R cell survival. cell to promotefound cancer prostate been box A1) has (Forkhead homeobox 1) FoxA1 and (NK3 iNKX3-1 factors transcription other and of AR work composing net regulatory transcriptional a via of RAB3B overexpression Moreover, patients. cancer tate pros in overexpressed is and ily fam GTPase RAB ofmember the RAB3B upregulated. is that signature gene high positive/AR CDK2AP1 tumor-suppressors putative both ferent prostate cancer cell lines. cell cancer ferent prostate dif using vitro in growth cellular cell line. cell certain in re-expression AR with positively to correlate expression CDK2AP1 found also study same this since pathway AR the and cycle cell the between tion dependent on complex interac CDK2AP1 of effect the and vivo in studied not been has However, this NA U Cell growth anddifferentiation G biquitin mediated proteolysis 2 transport andmTOR transport signaling RAB3B /M transition and cell cycle cell and /M transition Myc regulation Pathways U Cell cycle is another ERG- another is and RAB3B and expression may be be may expression nknown 36,37 The reason why reason The V olume 15 Issue9 are upreg are is a is 36 ------

©2014 Landes Bioscience. Do not distribute. Downloaded by [University of Alberta] at 13:03 29 January 2015 www.landesbioscience.com expression regulation. expression c-myc than other functions suggesting of RNAs to bind avariety shown been has of proteins ily fam FUBP the since elucidated to be remains biology cancer roleprostate its in expression, tein or c-myc pro variables clinic-pathological with association any to document failed study the knowledge of any clinical or pathological staging information. information. staging or pathological clinical of any knowledge prior without assembled was block Each Instruments). (Beecher arrayer tissue of 714 a manual control for a total as using cores tissue prostate benign adjacent including patient per (2–6) cores cancer of two average an with (TMAs) microarrays tissue two onto assembled was complete cohort The records. on medical based of PCa died and therapy on hormonal while progressed who disease of metastatic evidence with patients as defined was (PCSM) mortality cancer-specific Prostate implementation. treatment of hormonal dates and mortality, cancer-specific survival, to overall regard in Tumour Registry Alberta the from collected follow-up was Clinical symptoms. obstructive relieve to TURP channel to require apy, progressed but subsequently monother as agonist by LH-RH 119), treated were who initially ( CRPC men with represented group second The AdvPCa. to asPCa/ therapy, no prior hormonal referred with of tumors ( first The subgroups. into two cohort the therapy, hormonal we subdivided with interaction and relation 2009. To the and 2005 assess between manipulation or hormonal radiotherapy by observation, expectantly managed and by TURP better PCa prognostication. PCa better achieving in analysis gene for combined need the underpin and PCa in AR ERG and between cooperatively strong the with ing keep in are findings Our more aggressively. managed be should and risk athigher-mortality are tumors high ERG-positive/AR Patients with progression. PCa AR-mediated ERGin and/or implicated pathways affecting modules acting inter into non-random grouped functionally be can these show that and profile expression high ERG-positive/AR with associated signatures gene identifies We mortality. further overall as well as of PCa-specific terms in progression to PCa association in overexpression AR ERG and ing combin tumors of prostate subtype molecular cancer. prostate in expressed quently fre to be and transcription proto-oncogene c-myc to regulate found been had protein which a encodes that signature gene high positive/AR ERG- upregulated protein 1) an is binding FUBP1 For instance, of expression. gene regulation in implicated are The study cohort consisted of 312 men diagnosed with PCa PCa with of 312 consisted cohort men diagnosed study The construction microarray tissue and population Study In conclusion, we characterize and validate a validate and conclusion, we characterize In signatures gene high ERG-positive/AR Other Materials and Methods and Materials 39 (far-upstream element element (far-upstream

39 Although Although n =193), consisted - - - - -

deaths (HR:3.3 [1.9–5.6], (HR:3.3 deaths ERG-positive/high with samples 4. Figure A C R ancer Biology& Therapy expression profile. n = Kaplan–Meier survival curve (Swedish cohort: GSE8402) showing that PCa PCa that showing GSE8402) cohort: (Swedish curve survival Kaplan–Meier - - to cancer specific mortality in the Swedish cohort Swedish the in mortality specific to cancer ERG, GS, of analysis Table 3. Multivariate previously demonstrated in Sicar et Sicar in demonstrated previously was by immunohistochemistry assessed as cancer sion prostate in protein expres AR and status amplification gene AR between correlation The stain. counter hematoxylin following detection for HRP used was Microsystems) (Leica kit Detection Refine (sc-7305)AR441 Bond Polymer for 15 dilution. ata1:200 min clone Cruz Santa from antibody monoclonal mouse receptor androgen with incubated were then Slides Solution 2. Retrieval Epitope Leica using min for 30 retrieval heat-induced antigen to were subjected sections paraffin-embedded formalin-fixed thick µm Four Microsystems). (Leica platform Bond Max Leica assessed according to the 2005 ISUP criteria. ISUP 2005 to the according assessed was GS slides. initial on the TAB) and (SAH pathologists study the predominant two patterns of PCa were sampled. ERG were sampled. of PCa patterns two predominant the described. immunohistochemistry Medicine. of Faculty of Calgary, atUniversity board review institutional of the approval with were obtained data pathological and Clinical All Histological diagnosis of TMA cores were confirmed by two by two were confirmed cores of TMA diagnosis Histological analysis Pathological ERG immunohistochemistry was performed as previously previously as performed was ERG immunohistochemistry by assessment expression protein AR and ERG Gleason (≤7 >7) vs. Gleason = 4.25E-6) compared with PCa samples with ERG-negative/low ERG-negative/low with samples PCa with compared P =4.25E-6)

ERG/ ERG 13 A AR immunohistochemistry was performed on performed was immunohistochemistry AR R A R A R e xpression profile are at higher risk of cancer specific specific cancer of risk higher at are profile xpression 1.39 (0.78–2.45) 0.89 (0.62–1.27) 3.3 (2.44–4.47) 3.3 2.0 (0.97–4.1) HR (CI)

A al. R , and ERG/ , and 40 41 A For each patient, patient, For each R o verexpression verexpression 6.00e–15 P value 0.2549 0.5289 0.0575 1125 -

©2014 Landes Bioscience. Do not distribute. Downloaded by [University of Alberta] at 13:03 29 January 2015 rized as high vs. other lower intensities ( lower other intensities vs. high as rized catego was immunohistochemistry AR control. internal as acting cells, endothelial in expressed consistently and strongly sion was to define a molecular signature for ERG and AR for ERG and signature amolecular to define 0–2. grades intensity immunostaining with those were expressers PCa low AR the 3, and grade intensity nostaining immu with those as were designated expressers PCa AR high The stroma. the in staining non-specific the than no higher intensity staining with samples to those assigned 0was 3. Grade 1 and grade between intensities 2to staining grade and staining, cell lial endothe and stromal non-specific faint above intensity staining lowest 1to the grade sample, of agiven intensity highest 3 to the of agrade assigned who pathologists by two of 0–3 scale a grading on semi-quantitatively graded was intensity immunostaining AR 1126 assay. hybridization situ in fluorescent apart break with correlation on previous based negative vs. positive as assessed was immunohistochemistry ERG-negative, high vs. low AR and ERG-positive/AR high vs. vs. high ERG-positive/AR and low AR vs. high ERG-negative, vs. ERG-positive between expressed differentially genes nature sig to filter used was curve under ROC area Rpackage. cluster implemented in by PAM clustering determined as mRNA AR high 190 and expressed (FISH) hybridization situ in fluorescent by determined as (ERG-positive) were ERG rearranged samples Forty-four GSE8402). number identification accession GEO the using http://www.ncbi.nlm.nih.gov site Omnibus Expression NCBI Gene the through accessed be can cohort this regarding Figure 5. negative expression in a PCa (note endothelial cells positivity acting as internal control). internal as acting positivity cells (note endothelial aPCa in expression negative expression in a Gleason score 6 PCa. ( The Swedish GSE8402 cohort ( cohort GSE8402 Swedish The signature of ERG/AR Development

Representative images of ERG and and ERG of images Representative ERG gene rearrangement detected by detected rearrangement gene C ) n A = 281) data sets was used used was =281) sets data R h A Fig. igh expression in a Gleason score 8 PCa. ( 8PCa. score aGleason in expression igh R i mmunohistochemistry in prostate cancer. ( cancer. prostate in mmunohistochemistry

5 ). Specifically, the the Specifically, ). 42 15 (Information (Information ERG expres ERG C ancer Biology& Therapy - - - - - 0.05 was considered significant. considered was 0.05 < aPvalue tests statistical all In disease. to lethal variables ciate to GS asso and ERG, AR including models regression Cox using conducted was analysis Multivariate disease. resistant of castrate development till time and mortality, overall of PCSM each and expression AR ERG and between associations to test analyses for survival used was test log-rank the with Meier along approach Kaplan– The protein expression. AR ERG and between ciations for asso to test used was test Chi-square variables. continuous for ranges and means as and variables, for categorical centages PCa. in overexpression AR of ERG and combination the behind ogy biol systems the understand to better genes these work between by the Movember Foundation (B2013-01). Movember Foundation by the funded proudly is and Canada cancer by Prostate supported also work was This (T.A.B.). Award YoungFoundation Investigator Interaction plug-in in Cytoscape plug-in in Interaction Functional Reactome subgroup. The high ERG-positive/AR the 152 in aresult; As were identified genes genes. significant filter to athreshold as AUC low used PCa. 0.7 was ERG-negative/AR Patient characteristics were presented as frequencies and per and frequencies as were presented Patient characteristics analysis Statistical This work was supported in part by the Prostate Cancer Cancer Prostate by the part in supported work was This were disclosed. of interest conflicts No potential

D ) ERG-positive expression in a Gleason score 6 PCa. ( 6PCa. score aGleason in expression ) ERG-positive Disclosure of Potential Conflicts of Interest Conflicts ofPotential Disclosure A) A R l ow expression in a Gleason score 6 PCa, ( 6PCa, score aGleason in expression ow Acknowledgments 29 was used to build the net the to build used was V olume 15 Issue9 B ) A E R h ) ERG- igh igh - - - - -

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