ABSTRACT Background Chronic inflammation is the most common histological feature in Benign Prostatic Hyperplasia (BPH), and T cells are a key component of immune infiltrate. Advanced BPH is commonly associated with the formation of nodules, but it remains unclear whether a link exists among T cell infiltration, nodular development, and BPH progression. Using a Toxoplasma gondii ( T. gondii ) model and human specimens, we characterize the subtypes of T cells present during prostatic hyperplasia and their association with nodular development of the prostate. Methods Male CBA/j mice were intraperitoneally infected with T. gondii parasites, and flow cytometry was performed on the prostate to quantify the number of CD4+ and CD8+ T cells. Histology was used to score microglandular hyperplasia (MGH), and immunofluorescence was used to quantify and examine the locality of CD4+ and CD8+ T cells and compared that to human BPH tissue. Results We found that infecting male mice with T. gondii resulted in an increase of both CD4+ and CD8+ T cells in the prostate acutely and that CD8+ cells remained sustained at chronically. We also established the presence of glandular nodule formation at this timepoint through hematoxylin and eosin (H&E) staining. Immunofluorescence revealed that CD8+ cells were found proximal to forming glandular nodules relative to non-nodular glands. We also found more CD8+ cells localized to non-nodular glands in nodular BPH tissue versus non-nodular BPH tissue. Finally, we discovered a higher prevalence of CD8+ cells in T. gondii IgG+ patients than in IgG-patients. All T. gondii IgG+ patients exhibited nodular BPH, whereas all but one IgG-patient exhibited non-nodular BPH. Conclusions This study is the first to investigate the presence and location of CD4+ and CD8+ T cells within nodular and non-nodular BPH glands. We found an association of the presence of CD8+ T cells with nodular progression. This association held true in human prostate tissue. Translationally, CD8+ T cells may enhance nodular BPH progression, and T. gondii infection may promote this CD8+ T cell-mediated response.

Objectives:Benign Prostatic Hyperplasia (BPH) is the non-cancerous enlargement of the prostate accompanied by lower urinary tract symptoms, affecting 50% of men by the age of 501,2. Advanced highly symptomatic BPH exhibits large epithelial glandular nodules with microglandular/atypical adenomatous hyperplasia, but how these features form is unknown3. Our lab has reported that the common parasite Toxoplasma gondii can infect the prostate and induce glandular nodule formation in mice3. The objective of this study is to determine if T. gondii exposure in humans correlates to BPH and nodule formation and if it induces urinary dysfunction concurrent in the mouse model. Methods:We assessed Toxoplasma exposure by serum ELISA in patients with BPH and non-BPH donor controls, and compared seropositivity rates between the groups. We further assessed the histopathology of these patients for the presence of inflammation and epithelial glandular nodule formation and compared Toxoplasma positive and negative samples. We determined voiding function in Toxoplasma-infected mice between 14 and 60 days of infection with void spot with Void Whizzard software. Results:Men diagnosed with BPH are more likely to be seropositive for Toxoplasma than age-matched undiagnosed donorcontrols. In addition, BPH patients that are seropositive for Toxoplasma are more likely to exhibit glandular nodule formation with microglandular / adenomous hyperplasia than seronegative BPH patients. In animal studies, Toxoplasma infection results in abnormal void patterns concurrent with microglandular hyperplasia and nodule formation. Conclusions:These results suggest that Toxoplasma may be contributing to BPH pathology and lower urinary tract dysfunction in both humans and mice, opening new insights into the development of this important disease. The results also serve to further characterize this model of prostatic hyperplasia and define it as a potential urinary dysfunction model.

IntroductionThe prostate is densely innervated like many visceral organs and glands. However, studies to date have focused on sympathetic and parasympathetic nerves and little attention has been given to the presence or function of sensory nerves in the prostate. Recent studies have highlighted a role for sensory nerves beyond perception of noxious stimuli, as anterograde release of neuropeptides from sensory nerves can affect vascular tone and local immune responses.MethodsTo identify the degree of sensory innervation in the prostate, we utilized state-of-the-art tissue clearing and microscopy to visualize sensory innervation in the different lobes of the mouse prostate. To determine whether sensory nerves have a role in regulating proliferation within the prostate, we used an intersectional genetic and toxin approach to ablate peptidergic sensory nerves systemically.ResultsWe found that sensory neurons are abundant in the prostate both in nerve bundles along the vasculature and as independent nerve fibers wrapped around prostatic acini in a net-like fashion. In addition to the dense innervation of the prostate, we found that Calca haploinsufficiency, the genotype control for our intersectional ablation model, results in a diminished level of Ki67 staining in the stromal compartment of the dorsal lobe and a diminishing Ki67 trend in other lobes.DiscussionThese findings suggest that sensory neurons might have developmental or homeostatic effects within the prostate. Further studies are warranted to assess the role of sensory neurons and the sensory neuropeptides on prostatic development and on proliferation in the presence of pro-inflammatory stimuli such as bacterial infection or tumor cells.

The majority of patients with benign prostate hyperplasia (BPH) exhibit chronic prostate inflammation and the extent of inflammation correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms are not clearly understood. We established a unique mouse model Prostate Ovalbumin Expressing Transgenic 3 (POET3) that mimics chronic non-bacterial prostatitis in men to study the role of inflammation in prostate hyperplasia. After the injection of ovalbumin peptide-specific T cells, POET3 prostates exhibited an influx of inflammatory cells and an increase in pro-inflammatory cytokines that led to epithelial and stromal hyperplasia. We have previously demonstrated with the POET3 model that inflammation expands the basal prostate stem cell (bPSC) population and promotes bPSC differentiation in organoid cultures. In this study, we investigated the mechanisms underlying the impact of inflammation on bPSC. We found that AR activity was enhanced in inflamed bPSC and was essential for bPSC differentiation in organoid cultures. Most importantly, we identified, for the first time, interleukin 1 receptor antagonist (IL-1RA) as a key regulator of AR in basal stem cells. IL-1RA was one of the top genes upregulated by inflammation and inhibition of IL-1RA abrogated the enhanced AR nuclear accumulation and activity in organoids derived from inflamed bPSC. The mirroring effects of IL-1RA recombinant protein and IL-1α neutralizing antibody suggest that IL-1RA may function by antagonizing IL-1α inhibition of AR expression. Furthermore, we established a lineage tracing model to follow bPSC during inflammation and under castrate conditions. We found that inflammation induced bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation in bPSC is sufficient for their proliferation and differentiation under androgen-deprived conditions. However, proliferation of the differentiated bPSC in the luminal layer significantly diminished with castration, suggesting inflammation may not maintain AR activity in stromal cells, as stromal cells deprived of androgen after castration could no longer provide paracrine growth factors essential for luminal proliferation. Taken together, we have discovered novel mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that contributes to prostate hyperplasia.

Structures and NMR analysis of novel ref-1 inhibitors APX2009 and APX2014. A. APX3330; NMR and HPLC as previously published.15-18 B. APX2009; HPLC: HPLC were performed using an Alltech Alltima column C18 5u, 250 x 5.6 mm, flow 1 mL/min at 40 .C. Elution was with a mobile phase of 15:10:75 water:A1:methanol where A1 was made using 700 mL of water, 300 mL methanol and 3mL trimethylamine to which phosphoric acid was added to bring the pH to 3.4. HPLC analysis showed a purity of >99%. NMR: 300 MHz NMR -conforms to structure. NMR (CDCl3) Î' 8.15 (m, 2H), 7.75 (m,2H), 6.2 (s, 1H), 4.1 (s, 3H), 3.6 (br d, 4H), 2.2 (t, 2H), 1.4 (m, 4H), 1.25 (br d, 4H), 0.85(t, 3H). B. APX2014; HPLC: HPLC analysis was performed as for APX2009, but using a Zorbax SB Phenyl C18 5u, 250 x 4.6 mm column. Elution was with a mobile phase of 25:10:65 water:A1:methanol where A1 was made using 700 mL of water, 300 mL methanol and 3mL trimethylamine to which phosphoric acid was added to bring the pH to 3.4. Flow 1 mL/min at 40 .C. and showed a purity of >99%. NMR: 300 MHz NMR -conforms to structure. NMR (CDCl3) Î' 8.8 (br s,1H), 8.1 (m, 2H), 7.75 (m, 2H), 6.7 (s, 1H), 4.15 (s, 3H), 3.9 (s, 3H), 2.2 (m, 2H), 1.4 (m, 2H), 0.85 (t, 3H).

Video of caspase 3 activity used to capture images used in quantification of caspase activation, indicating apoptosis induction. Representative video of UC3 cells treated with APX2009 as red indicator dye generated from Caspase 3 activity is shown overlayed with brightfield image for each treatment. Duration of the video is the 72 hour duration of the experiment, as quantified and shown in Figure 2. Representative stills are shown in supplementary figure 3.

Confirmation of APE1/Ref-1 and STAT3 expression in 3d and monolayer conditions in RP-B-O1 and RP-B-O2 cells. Basal growth conditions as described in the methods for each cell line were used for monolayer and 3D conditions. No significant differences in expression relative to actin were observed in either condition. Representatuive blot is shown in [A], and quantified data as the ratio of each protein to actin from 3 determinations is shown in [B,C].

APE1/Ref-1 localization in human tumors. Additional examples of APE1/Ref-1 immunofluorescence in human bladder cancer specimens at 10X and 40X. Lower power (10X) [A] demonstrates transition from nuclear localized APE1/Ref-1 in the epithelial compartment (Epi) to cytosolic staining in the invasive regions of a human tumor, in the muscularis (Musc) in a single image, with high power (40x) views showing the cellular localization [B,C]. Additional examples in high power are shown in [D], from 3 different specimens (1-3), exclusively nuclear staining in the epithelial compartment (Epi) and cytosolic staining in the invasive satellite lesions (INV).

Confirmation of cell death induction by caspase activity assay and PARP cleavage. Representative images for caspase activity via red fluorescence [A] for the data calculated and shown in Figure 2, each with matching brightfield images. Representative examples for T24 and UC3 cells are shown form cells treated with the growth-inhibitor EC50 concentrations for each drug, in each cell line. PARP cleavage was used to confirm the induction of apoptotic mechanisms by western blotting for cleaved PARP1 [B], with representative cell experiments in which UC3 cells were treated with EC50 and EC90 concentrations of each drug.

Legend for supplementary videos.

Abstract The TMPRSS2–ERG gene fusion and subsequent overexpression of the ERG transcription factor occurs in ∼50% of prostate tumors, making it the most common abnormality of the prostate cancer genome. While ERG has been shown to drive tumor progression and cancer-related phenotypes, as a transcription factor it is difficult to target therapeutically. Using a genetic screen, we identified the toll-like receptor 4 (TLR4) signaling pathway as important for ERG function in prostate cells. Our data confirm previous reports that ERG can transcriptionally activate TLR4 gene expression; however, using a constitutively active ERG mutant, we demonstrate that the critical function of TLR4 signaling is upstream, promoting ERG phosphorylation at serine 96 and ERG transcriptional activation. The TLR4 inhibitor, TAK-242, attenuated ERG-mediated migration, clonogenic survival, target gene activation and tumor growth. Together these data indicate a mechanistic basis for inhibition of TLR4 signaling as a treatment for ERG-positive prostate cancer.

The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function.

Abstract Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction–oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1–specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. Significance: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo.

Abstract More than one-half of prostate tumors have a chromosomal rearrangement that results in the overexpression of an oncogenic ETS family transcription factor. The most common fusion, TMPRSS2/ERG, results in expression of ERG, a protein that is not normally expressed in prostate epithelia. When ERG is expressed in prostate cells it is thought to bind to enhancer elements and regulate gene expression by recruiting transcriptional coactivators and/or corepressors. We have recently shown that the EWS protein acts as a coactivator for ERG in prostate cells and this interaction is required for ERG-mediated xenograft tumor growth. Interestingly, the EWS interaction may be the key requirement that separates oncogenic from nononcogenic ETS factors, as EWS only interacts with four ETS family members involved in prostate cancer gene rearrangements (ERG, ETV1, ETV4, and ETV5), but not with other ETS family members. This ETS/EWS interaction also indicates a common molecular mechanism involved in prostate cancer and Ewing’s sarcoma, a cancer caused by gene fusions that express chimeric EWS/ETS proteins. ERG also interacts with corepressors such as EZH2, a subunit of PRC2. We have recently found that the interaction between ERG and EZH2/PRC2 is regulated by a series of phosphorylation events on ERG. The MAP kinase ERK can bind a high-affinity docking sequence in ERG, resulting in phosphorylation of a nearby serine, S215. This phosphorylation event leads to a conformational change in ERG that allows ERK to phosphorylate a second serine, S96. S96 phosphorylation then disrupts the interaction between ERG and EZH2/PRC2, allowing ERG to activate gene expression. Together, the interaction of ERG with EWS and the regulation of ERG function by ERK-mediated phosphorylation, represent molecular mechanisms that could serve as targets for therapeutic intervention in ERG-positive prostate cancer. Citation Format: Vivekananda Kedage, Taylor R. Nicholas, Brady G. Strittmatter, Nagarathinam Selvaraj, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst. Regulation of ERG function in prostate cells by phosphorylation and interaction with Ewing’s sarcoma breakpoint protein EWS [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A023.

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology1 Apr 2017MP17-05 TOXOPLASMA GONDII INFECTS THE PROSTATE AND INDUCES MICROGLANDULAR HYPERPLASIA IN A MOUSE MODEL OF PROSTATIC HYPERPLASIA Darrelle Colinot, Tamila Garbuz, Maarten Bosland, William Sullivan, Gustavo Arrizabalaga, and Travis Jerde Darrelle ColinotDarrelle Colinot More articles by this author , Tamila GarbuzTamila Garbuz More articles by this author , Maarten BoslandMaarten Bosland More articles by this author , William SullivanWilliam Sullivan More articles by this author , Gustavo ArrizabalagaGustavo Arrizabalaga More articles by this author , and Travis JerdeTravis Jerde More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.594AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia. Several factors have been hypothesized to cause inflammation, yet the role each plays in the etiology of prostatic inflammation remains unclear. This study investigated a role for the common protozoan parasite Toxoplasma gondii in prostatic inflammation and established a novel mouse model. METHODS Male mice were infected intraperitoneally with green fluorescent protein (GFP)-expressing T. gondii parasites and prostatic infection was confirmed with parasite specific staining and GFP localization. The resulting prostatic inflammation was scored on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation. In addition, human sera from T. gondii IgG seropositive and seronegative male patients were tested for total prostate specific antigen (PSA) concentrations by ELISA. RESULTS We found that T. gondii infects the mouse prostate during systemic infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of microglandular hyperplasia in 60 day inflamed mouse prostates. Finally, T. gondii seropositive men have 5.08 times the odds of having an elevated PSA level (>4.0 ng/ml) than age-matched seronegative men. CONCLUSIONS We found that T. gondii infects the mouse prostate during systemic infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of microglandular hyperplasia in 60 day inflamed mouse prostates. Finally, T. gondii seropositive men have 5.08 times the odds of having an elevated PSA level (>4.0 ng/ml) than age-matched seronegative men. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e213 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Darrelle Colinot More articles by this author Tamila Garbuz More articles by this author Maarten Bosland More articles by this author William Sullivan More articles by this author Gustavo Arrizabalaga More articles by this author Travis Jerde More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

BACKGROUND:Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia and prostate cancer. Several factors have been hypothesized to cause inflammation, yet the role each may play in the etiology of prostatic inflammation remains unclear. This study examined the possibility that the common protozoan parasite Toxoplasma gondii induces prostatic inflammation and reactive hyperplasia in a mouse model.METHODS:Male mice were infected systemically with T. gondii parasites and prostatic inflammation was scored based on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation.RESULTS:We found that T. gondii infects the mouse prostate within the first 14 days of infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of proliferative inflammatory microglandular hyperplasia in inflamed mouse prostates.CONCLUSIONS:This study identifies the common parasite T. gondii as a new trigger of prostatic inflammation, which we used to develop a novel mouse model of prostatic inflammation. This is the first report that T. gondii chronically encysts and induces chronic inflammation within the prostate of any species. Furthermore, T. gondii-induced prostatic inflammation persists and progresses without genetic manipulation in mice, offering a powerful new mouse model for the study of chronic prostatic inflammation and microglandular hyperplasia.

A key feature of prostate cancer progression is the induction and activation of survival proteins, including the Inhibitor of Apoptosis (IAP) family member survivin. Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein that is essential in activating oncogenic transcription factors. Because APE1/Ref-1 is expressed and elevated in prostate cancer, we sought to characterize APE1/Ref-1 expression and activity in human prostate cancer cell lines and determine the effect of selective reduction-oxidation (redox) function inhibition on prostate cancer cells in vitro and in vivo. Due to the role of oncogenic transcriptional activators NFĸB and STAT3 in survivin protein expression, and APE1/Ref-1 redox activity regulating their transcriptional activity, we assessed selective inhibition of APE1/Ref-1's redox function as a novel method to halt prostate cancer cell growth and survival. Our study demonstrates that survivin and APE1/Ref-1 are significantly higher in human prostate cancer specimens compared to noncancerous controls and that APE1/Ref-1 redox-specific inhibition with small molecule inhibitor, APX3330 and a second-generation inhibitor, APX2009, decreases prostate cancer cell proliferation and induces cell cycle arrest. Inhibition of APE1/Ref-1 redox function significantly reduced NFĸB transcriptional activity, survivin mRNA and survivin protein levels. These data indicate that APE1/Ref-1 is a key regulator of survivin and a potentially viable target in prostate cancer.

Abstract The TMPRSS2-ERG gene fusion occurs in one-half of prostate tumors and results in expression of ERG, an ETS family transcription factor that promotes prostate tumorigenesis. Another 5-10% of prostate tumors have similar rearrangements that result in over-expression of other ETS family members such as ETV1, ETV4, and ETV5. However, not all ETS family members are oncogenic, and normal prostate cells express at least 15 of these other ETS factors. Therefore, it is important to understand mechanisms that differentiate oncogenic ETS factors from non-oncogenic ETS factors. We have recently discovered that ERG, ETV1, ETV4, and ETV5, and no other ETS factor can directly bind the protein EWS. This is striking, as EWS is fused to various ETS factors in the chromosomal rearrangements that cause Ewing’s sarcoma. We demonstrate that fusion of EWS to any ETS protein is sufficient for that protein to function like ERG in prostate cells. Furthermore, the EWS-ERG interaction is required for ERG to activate an oncogenic gene expression program and for ERG-mediated tumorigenesis. Therefore, these findings reveal a conserved oncogenic mechanism for prostate cancer and Ewing’s sarcoma. In prostate cancer, aberrant over-expression of an ETS factor that naturally interacts with EWS, brings EWS to ETS-bound regions. In Ewing’s sarcoma this interaction is forced by the presence of an EWS/ETS fusion protein. Therefore, this model predicts that treatments that target EWS function would be effective in both types of cancer. Citation Format: Vivekananda Kedage, Nagarathinam Selvaraj, Taylor R. Nicholas, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst. A role for the Ewing’s sarcoma breakpoint protein EWS in ERG-induced prostate tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3510. doi:10.1158/1538-7445.AM2017-3510