Prostate Cancer Genetic-susceptibility Locus on Chromosome ... · Prostate cancer is the most frequent cancer in North American men and the second leading cause of cancer-related

Prostate Cancer Genetic-susceptibility Locus onChromosome 20q13 is Amplified and Coupled to AndrogenReceptor-regulation in Metastatic Tumors

David P. Labb�e1,2, Dawid G. Nowak4, Genevi�eve Deblois1,3, Laurent Lessard5, Vincent Gigu�ere1,2,3,Lloyd C. Trotman4, and Michel L. Tremblay1,2,3

AbstractThe 20q13 chromosomal region has been previously identified as the hereditary prostate cancer genetic-

susceptibility locus on chromosome 20 (HPC20). In this study, the 20q13 region was shown to be frequentlyco-amplifiedwith the androgen receptor (AR) inmetastatic prostate cancer. Furthermore, the AR signaling axis, whichplays an essential role in the pathogenesis of prostate cancer, was demonstrated to be central to the regulation of the20q13 common amplified region (CAR). High-resolution mapping analyses revealed hot spots of AR recruitment toresponse elements in the vicinity ofmost genes located on the 20q13CAR.Moreover, amplification ofAR significantlyco-occurred with CAR amplification on 20q13 and it was confirmed that the majority of AR-bound genes on the20q13 CAR were indeed regulated by androgens. These data reveal that amplification of the AR is tightly linked toamplification of the AR-regulated CAR region on 20q13. These results suggest that the cross-talk between geneamplification and gene transcription is an important step in the development of castration-resistantmetastatic disease.

Implications: These novel results are a noteworthy example of the cross-talk between gene amplification and genetranscription in the development of advanced prostate cancer.Visual Overview: http://mcr.aacrjournals.org/content/early/2014/02/07/1541-7786.MCR-13-0477/F1.large.jpg.Mol Cancer Res; 12(2); 184–9. �2013 AACR.

IntroductionProstate cancer is the most frequent cancer in North

American men and the second leading cause of cancer-related deaths. Age, African ancestry, and diet are amongthe known risk factors contributing to prostate cancerdevelopment. In addition, evidence based on case–control,cohort, twin, and family studies demonstrates that prostatecancer is also a genetic disease.Men with a history of familialor hereditary prostate cancer have a 2- to 7-fold increased risk

of developing the disease (1). In fact, a positive family historyis one of the strongest risk factors for prostate cancer and it islinked to approximately 10% to 15% of cases (2).At least 15 different loci located on 10 distinct chromo-

somes have been linked to hereditary prostate cancer (3), butthere is no single highly penetrant prostate cancer suscepti-bility gene identified to date. Instead, the heredity of prostatecancer is attributable to a largenumber of genes that have smalleffect(s) on their own, further illustrating the heterogeneity ofthe disease (2). In addition, recent genome-wide associationstudies revealed a minimum of 30 common genetic lociassociated with prostate cancer risk, making this disease themost prolific of all cancers in term of common susceptibilityloci. However, there is no clear evidence that the various lociassociated with the risk of developing prostate cancer are alsoassociated with either aggressiveness or mortality (4).Current techniques enable the detection and treatment of

most early stage tumors. Still, androgen-deprivation therapytargeting androgen receptor (AR) transcriptional activity hasremained the first line of treatment for advanced disease sinceits description in 1941, although it ultimately leads toincurable castration-resistant metastatic prostate cancer(CRMPC). Strikingly, most CRMPCs still rely on the ARtranscriptional activity due to different adaptive mechanisms,such as AR mutation, ligand-independent AR activation,endogenous androgen synthesis, or evenAR amplification (5).

Authors' Affiliations: 1Goodman Cancer Research Centre; 2Departmentof Medicine, Division of Experimental Medicine; 3Department of Biochem-istry and Oncology, McGill University, Montr�eal, Qu�ebec, Canada; 4ColdSpring Harbor Laboratory, NY; and 5Department of Molecular Oncology,John Wayne Cancer Institute at St. John's Health Center, Santa Monica,California

Note: Supplementary data for this article are available at Molecular CancerResearch Online (http://mcr.aacrjournals.org/).

Corresponding Authors:Michel L. Tremblay, GoodmanCancer ResearchCentre, McGill University, 1160 Pine Avenue, Room 617, Montr�eal, QC,Canada H3A 1A3. Phone: 514-398-8280; Fax: 514-398-6769; E-mail:[email protected]; and Lloyd C. Trotman, Cold Spring HarborLaboratory, 1 Bungtown Road, James Building, Room 210, Cold SpringHarbor, NY 11724. Phone: 516-367-5054; Fax: 516-367-8454; E-mail:[email protected]

doi: 10.1158/1541-7786.MCR-13-0477

�2013 American Association for Cancer Research.

MolecularCancer

Research

Mol Cancer Res; 12(2) February 2014184

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In this study, we report that a region of the previouslyidentified hereditary prostate cancer genetic-susceptibilitylocus located on chromosome 20 (HPC20; 6) is frequentlycoamplified with the AR in metastatic prostate cancertumors. Interestingly, we found that this region is also ahot spot for AR recruitment to chromatin.We show that ARbinds and regulates most genes within the common ampli-fied region (CAR), suggesting that the coordinated copynumber gain and increased transcriptional output of the20q13 CAR might be an important event leading to thedevelopment of CRMPC.

Materials and MethodsCopy number alteration in prostate cancerAnalysis of copy number alteration on the 20q chromo-

somal arm is based on the published copy number profilesfrom 181 primary and 37 metastatic prostate tumors (7)using the Nexus Copy Number software v6.0 (BiodiscoveryInc.). Circos graph was performed using the R software andRCircos package (8).

Cell cultureLNCaP cells were purchased from the American Type

Culture Collection and maintained in RPMI-1640 medium(Wisent) supplemented with 10%FBS, L-glutamine, and 50mg/mL gentamycin. The synthetic androgen analog R1881was obtained from PerkinElmer. For androgenic stimulationassays, cells were first androgen deprived in phenol-freeRPMI 1640 supplemented with 5% charcoal-stripped FBS,L-glutamine, and 50 mg/mL gentamycin. After 48 hours,medium was refreshed and R1881 or ethanol (vehicle) wasadded for the indicated period.

ChIP assays and ChIP-on-chip analysis on chr.20 tiledarrayChromatin was prepared from LNCaP cells exposed to 1

nmol/L R1881 or vehicle for 4 hours. Chromatin immuno-precipitation (ChIP) was performed as described previously(9) using antibodies specific to AR (mouse monoclonal anti-AR from Lab Vision and BDBiosciences). Amplification andlabeling of AR-bound ChIP fragments was performed asdescribed previously (9). Hybridization was carried out ona custom-designed tiled array fromAgilent covering the q armof chr.20 at a resolutionof 150bp and analyzed fromassemblyhg18, using the Feature Extraction 10 alignment program andChIP Analytics 3.1 program for peak detection (Agilent).

Analysis of gene expressionTotal RNA extraction, reverse transcription, and quanti-

tative real-time PCR were performed as already described(9). For MIR645 reverse transcription, the qScript micro-RNA cDNA synthesis kit was used (Quanta Biosciences).The primer sequences used can be found in SupplementaryTable S1. Threshold cycle numbers were calculated using thesecond derivative maximum obtain with the LightCycler480 software version 3.5 (Roche). Data were normalizedaccording toRPLP0 levels (Supplementary Table S1).mRNAexpression Z-scores were obtained from the cBIO portal

(www.cbioportal.org) using the dataset by Taylor and collea-gues (7). mRNA expression was represented as the Z-score ofprostate cancer samples versus normal prostate samples. Then,the average Z-scores from primary samples were subtractedfrom the average Z-scores from metastatic samples.

Statistical analysisStatistical analyses were performed with the Prism 5.0

GraphPad Software. The significance of gene expressionmodulation following R1881 treatment was assessed by theMann–Whitney test. The differences in the risk of biochem-ical relapse were computed using the log-rank test.

ResultsGiven the addiction of prostate cancer cells to AR tran-

scriptional activity, androgen-deprivation therapy invariablyresults in adaptive mechanisms that maintain AR signaling.Accordingly,AR gene amplification was observed exclusivelyin CRMPC samples (7). In addition, metastatic tumorsdisplayed an array of DNA copy number alterations (CNA)scattered throughout the genome that can possibly synergizewith AR gene amplification. Analysis of metastatic prostatecancer samples revealed frequent coamplification (�35%)of several genomic regions on eight different chromosomeswith the AR gene (Fig. 1). Surprisingly, our analysis uncov-ered that the AR is significantly coamplified with a regionlocated on the 20q chromosome arm, previously identified asHPC20 (6), uniquely in metastatic tumors (SupplementaryFig. S1). We determined that the CAR on 20q13 is locatedwithin the HPC20, which is flanked by the markersD20S887 and D20S196 (Figs. 2A and B, orange bars).

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Figure 1. AR is coamplified with a region within the HPC20 in metastaticprostate cancer. Circos plot of genome-wide coamplification events inAR amplified metastatic samples at P � 0.0125. The 20q13, within theHPC20 locus, is the sole region associated with AR amplification onchromosome 20. A total of eight different chromosomes possess at leastone locus significantly associated with AR amplification.

AR Regulation of the 20q13 Amplicon

www.aacrjournals.org Mol Cancer Res; 12(2) February 2014 185




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Figure2. The20q13CAR is rich inARbinding sites and is coamplifiedwith theAR. A, representationof theamplified (blue) anddeleted (red) regions on the entire20q chromosomal arm for patients demonstrating amplification of the 20q13 CAR (orange bars) in primary and metastatic tumors. Localization of theAR-bound segments identifiedbyChIP-on-chip analysis is also indicated (vertical red lines,P� 10�5). B, zoomed representation of panel A. C, overviewof the20q12–20q13.33 locus revealed that the genomic region significantly associated with AR coamplification in metastatic cancer falls within the AR-densebinding region identified within the HPC20 (green).

Labb�e et al.

Mol Cancer Res; 12(2) February 2014 Molecular Cancer Research186




Owing to the frequent coamplification of the 20q13CAR with the AR in metastatic prostate cancer, we inves-tigated whether this region was subjected to AR-transcrip-tional regulation. We performed genomic location analysisof AR recruitment to chromatin in the androgen-sensitiveLNCaP cell line, using a tiled array covering the q arm ofhuman chromosome 20. Cells were maintained in asteroid-depleted medium for 48 hours before stimulationwith the synthetic androgen analog R1881 for 4 hours.ChIP-on-chip analyses reveal 245 segments bound by theAR, mostly in nonpromoter regions (Supplementary TableS2, P � 10�5). Strikingly, the 20q13 CAR is a local hotspot in AR binding sites (Figs. 2A and B, vertical red lines).Refined analysis of this locus uncovered that AR coampli-fication with the 20q13 is restricted to the CAR inmetastatic prostate cancer, which also corresponds to aregion rich in AR binding sites (Fig. 2C).Fourteen genomic segments bound by AR in LNCaP cells

were associated with 10 of the 16 genes (62.5%) presentwithin the 20q13 CAR (Fig. 3A). To validate the relevanceof this AR binding profile, we examined the impact of ARactivation on the expression of amplicon-resident genes.R1881 treatment resulted in the significant modulation of7 of the 10 genes that we found associated with AR-boundsegments (Fig. 3B, P < 0.01). The three remaining geneswere either not affected by R1881 treatment (PARD6B),were not expressed in LNCaP cells (LOC284751), or wereimpossible to distinguish from a chimeric transcript withspecific primers (UBE2V1 vs. TMEM189-UBE2V1; Fig.3B). Interestingly, we found that the expression level of mostof the genes within the 20q13 CAR was increased inmetastatic samples (Fig. 3C). In addition, analysis of thethree metastatic samples positives for AR and CAR coam-plification for which clinical survival data were collected (7)demonstrate significant earlier biochemical recurrence com-pared with patients withoutAR and CAR amplification (Fig.3D). Together, these results suggest that AR, through itsamplification/activation, could synergistically enhance theexpression of genes within the 20q13 CAR in advanceddisease and significantly alter patient's prognosis whencoamplified with the CAR.

DiscussionGenetic linkage studies identified several susceptibility

loci for type II diabetes (10, 11) and obesity (12) mappingto theD20S196marker located on the 20q13 chromosomalregion. In addition, this region, flanked by the markersD20S196 and D20S887 (HPC20), has been described asa hereditary prostate cancer susceptibility locus (6). Inter-estingly, we and others have shown that the proteintyrosine phosphatase 1B (encoded by PTPN1), which islocated in the vicinity of the D20S196 marker and is part ofthe CAR, is indeed implicated in type II diabetes andobesity (13) and plays a tumor-promoting role in prostatecancer (9).In this study, we further demonstrate that the 20q13

chromosomal region is significantly amplified in meta-

static prostate cancer. Notably, this region encodes twotranscription factors, namely SNAI1 and CEBPB. SNAI1is an important mediator of the epithelial-mesenchymaltransition, a critical event in the metastatic process (14),and whose expression mediates cell survival and inhibitscellular senescence in metastatic prostate cancer cell lines(15). On the other hand, CEBPB is a recognized oncogenein Ras-mediated tumorigenesis (16). In addition, the20q13 CAR encodes MIR645, a member of the micro-RNA family that regulates gene expression posttranscrip-tionally. Beside a single report suggesting that the coex-pression of MIR410 and MIR645 is negatively associatedwith overall survival in advanced serous ovarian cancer(17), the role of MIR645 in cancer remains unknown.Similarly, a recurrent lung cancer amplicon located at14q13.3 was found to encode three transcription factors,namely TTF1/NKX2-1, NKX2-8, and PAX9. Remarkably,although the overexpression of a single transcription factordid not modify the proliferation of premalignant lungepithelial cell, overexpression of any pairwise combinationled to a major increase in their tumorigenic potential (18).Together, the altered transcriptional output mediated bythe coordinated DNA copy number gain of SNAI1,CEBPB, and MIR645 might contribute to a global tran-scriptional rewiring process, ultimately resulting in theincreased tumor aggressiveness observed in patients bear-ing the 20q13 CAR.A noteworthy feature of the 20q13 CAR is its extensive

regulation by AR. ChIP-on-chip analysis using the andro-gen-sensitive LNCaP cell line revealed AR binding in thevicinity of a large proportion of genes within the 20q13CAR (Fig. 3A). Importantly, this result was not biased bychromosomal abnormalities because LNCaP cells do nothave CNA in the 20q13 region (19). Surprisingly, mostprotein-coding transcripts from AR-bound genes weresensitive to R1881 treatment (Fig. 3B). As previouslydescribed, PTPN1 mRNA expression was strongly regu-lated by the AR (9). We also identified several novel AR-regulated genes within the 20q13 CAR with functions yetto be described in the prostate, including the solute carrierfamily 9, member 8 (SLC9A8), the spermatogenesis-associated protein 2 (SPATA2), the ring finger protein114 (RNF114), and the activity-dependent neuroprotec-tor (ADNP). Interestingly, the breast cancer amplifiedsequence 4 (BCAS4) was modestly but significantly reg-ulated by R1881. Finally, we also describe CEBPB(encoding C/EBPb) as an AR-regulated target. Zhangand colleagues recently demonstrated that C/EBPb caneffectively transactivate the prostate-specific antigen(PSA) promoter, which is regulated by androgen responseelements in the absence of androgen. However, increasedC/EBPb expression results in a decreased transactivationof the PSA promoter in the presence of androgen. Incontrast, AR activation results in an increased C/EBPbtranscriptional activity on CCAAT enhancer bindingprotein elements (20). This interesting cross-talk, togeth-er with the fact that AR-regulation of the 20q13 CAR isaccompanied by AR coamplification, supports a complex






transcriptional rewiring in a significant subset of meta-static tumors.In summary, we report the frequent amplification of the

20q13 chromosomal region in metastatic prostate cancer, a

region that had been previously identified as a hereditaryprostate cancer susceptibility locus. The extensive regulationof genes within the 20q13 CAR by AR, some of whichalready associated with oncogenic functions, suggests that

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Figure 3. The 20q13 CAR isandrogen regulated, upregulatedin metastatic disease, andassociatedwith earlier biochemicalrecurrence when coamplified withthe AR. A, binding profile of the ARfrom ChIP-on-chip analysisperformed in R1881-treatedLNCaP cells on a high resolutiontiled array covering the 20qchromosomal arm revealed that amajority of genes within the 20q13CAR possess AR binding sites intheir vicinity. B, R1881 treatment(10 nmol/L, 24 hours) modulatesthe mRNA-expression level ofmost genes within the 20q13 CARthat were associated with ARbinding sites in their vicinity (Mann–Whitney test, �P < 0.01 comparedwith vehicle; N ¼ 3, �SEM). C,genes within the CAR arepreferentially upregulated inmetastatic samples comparedwithprimary samples as demonstratedby the difference between theaverages of mRNA Z-scores(primary samples, N ¼ 109;metastatic samples,N¼ 19). D, therisk of biochemical relapse issignificantly higher in patientsharboring AR and CARcoamplifications (N ¼ 3) comparedwith patients with neither regionsamplified (N ¼ 169) (log-rank test;CARAmp, N ¼ 10; ARAmp, N ¼ 15).

Labb�e et al.

Mol Cancer Res; 12(2) February 2014 Molecular Cancer Research188




the highly specific coamplification of this chromosomalregion with the AR might synergize and contribute toincreased tumor aggressiveness and to the development ofmetastatic disease. These findings reflect the fact that ARamplification is not frequently seen at diagnosis but is verycommon in advanced therapy-resistant diseases. Thus, likeAR amplification status, AR–CAR amplification statusshould bemost informative as marker for disease progressionafter therapeutic intervention. These results may also reflecta potential example of the amplification of a locus afterenhanced transcriptional activity at that locus. Finally, theseresults justify further investigation to address the respectiveroles of the different genes within the 20q13 CAR.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

Authors' ContributionsConception and design: D.P. Labb�e, L. Lessard, V. Gigu�ere, L.C. Trotman,M.L. TremblayDevelopment of methodology: D.P. Labb�e, D.G. Nowak, L.C. TrotmanAcquisition of data (provided animals, acquired and managed patients, providedfacilities, etc.): D.P. Labb�e, G. DebloisAnalysis and interpretation of data (e.g., statistical analysis, biostatistics, compu-tational analysis): D.P. Labb�e, D.G. Nowak, G. Deblois, L.C. Trotman

Writing, review, and/or revision of the manuscript: D.P. Labb�e, D.G. Nowak,L. Lessard, V. Gigu�ere, L.C. Trotman, M.L. TremblayAdministrative, technical, or material support (i.e., reporting or organizing data,constructing databases): D.P. Labb�e, G. Deblois, L.C. TrotmanStudy supervision: V. Gigu�ere, L.C. Trotman, M.L. Tremblay

AcknowledgmentsThe authors thank Serge Hardy and Kelly-Anne Pike for helpful discussions and

Noriko Uetani for technical assistance with figure design and drawing.

Grant SupportD.P. Labb�e is a recipient of a Canadian Institute of Health Research (CIHR)

Frederick Banting and Charles Best Doctoral Research Award and a CIHR/Fonds derecherche du Qu�ebec–Sant�e Training Grant in Cancer Research FRN53888 of theMcGill Integrated Cancer Research Training Program. G. Deblois is supported by aPredoctoral Traineeship Award (W81XWH-10-1-0489) from theU.S.Department ofDefense Breast Cancer Research Program. This work was supported by CIHRoperating grants to V. Gigu�ere (MOP-64275) and M.L. Tremblay (MOP-62887)as well as a U.S. Army Department of Defense Award (#W81XWH-09-1-0259), aProstate Cancer Canada Grant (#02013-33) and a Jeanne and Jean-Louis LevesqueChair in Cancer Research to M.L. Tremblay, and by grants to L.C. Trotman from theNIH (CA137050), the Department of the Army (W81XWH-09-1-0557), and theRobertson Research Fund of Cold Spring Harbor Laboratory.

The costs of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be herebymarked advertisement in accordance with18 U.S.C. Section 1734 solely to indicate this fact.

Received September 9, 2013; revised November 20, 2013; accepted December 3,2013; published OnlineFirst December 30, 2013.

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2014;12:184-189. Published OnlineFirst December 30, 2013.Mol Cancer Res David P. Labbé, Dawid G. Nowak, Geneviève Deblois, et al. in Metastatic Tumors20q13 is Amplified and Coupled to Androgen Receptor-regulation Prostate Cancer Genetic-susceptibility Locus on Chromosome

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Prostate Cancer Genetic-susceptibility Locus on Chromosome ... · Prostate cancer is the most frequent cancer in North American men and the second leading cause of cancer-related