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TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer Alexandra M

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TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer Alexandra M Published OnlineFirst May 29, 2018; DOI: 10.1158/1078-0432.CCR-18-0653 Cancer Therapy: Preclinical Clinical Cancer Research TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer Alexandra M. Blee1,2, Yundong He1, Yinhui Yang1,3, Zhenqing Ye4, Yuqian Yan1, Yunqian Pan1, Tao Ma4, Joseph Dugdale1, Emily Kuehn1, Manish Kohli5, Rafael Jimenez6, Yu Chen7, Wanhai Xu3, Liguo Wang4, and Haojie Huang1,8,9 Abstract Purpose: Deletions or mutations in PTEN and TP53 tumor xenografts, and allografted mouse tumors. Trends were eval- suppressor genes have been linked to lineage plasticity in uated in TCGA, SU2C, and Beltran 2016 published patient therapy-resistant prostate cancer. Fusion-driven overexpres- cohorts and a human tissue microarray. sion of the oncogenic transcription factor ERG is observed in Results: Transgenic ERG expression in mice blocked Pten/ approximately 50% of all prostate cancers, many of which also Trp53 alteration–induced decrease of AR expression and harbor PTEN and TP53 alterations. However, the role of ERG downstream luminal epithelial genes. ERG directly suppressed in lineage plasticity of PTEN/TP53–altered tumors is unclear. expression of cell cycle–related genes, which induced RB Understanding the collective effect of multiple mutations hypophosphorylation and repressed E2F1-mediated expres- within one tumor is essential to combat plasticity-driven sion of mesenchymal lineage regulators, thereby restricting therapy resistance. adenocarcinoma plasticity and maintaining antiandrogen sen- Experimental Design: We generated a Pten-negative/Trp53- sitivity. In ERG-negative tumors, CDK4/6 inhibition delayed mutated/ERG-overexpressing mouse model of prostate cancer tumor growth. and integrated RNA-sequencing with ERG chromatin immu- Conclusions: Our studies identify a previously undefined noprecipitation-sequencing (ChIP-seq) to identify pathways function of ERG to restrict lineage plasticity and maintain regulated by ERG in the context of Pten/Trp53 alteration. We antiandrogen sensitivity in PTEN/TP53–altered prostate can- investigated ERG-dependent sensitivity to the antiandrogen cer. Our findings suggest ERG fusion as a biomarker to guide enzalutamide and cyclin-dependent kinase 4 and 6 (CDK4/6) treatment of PTEN/TP53-altered, RB1-intact prostate cancer. inhibitor palbociclib in human prostate cancer cell lines, Clin Cancer Res; 1–15. Ó2018 AACR. 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Introduction Medicine, Rochester, Minnesota. 2Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Castration-resistant prostate cancers respond to current anti- Minnesota. 3Department of Urology, the Fourth Hospital of Harbin Medical androgen therapies with variable levels of success (1), in part, due University, Harbin, Heilongjiang, China. 4Division of Biomedical Statistics and to extensive genetic heterogeneity (2–4). While mechanisms of Informatics, Department of Health Sciences Research, Mayo Clinic College of androgen receptor (AR) pathway restoration and compensation Medicine, Rochester, Minnesota. 5Department of Oncology, Mayo Clinic College are well documented, adenocarcinoma cell lineage plasticity and 6 of Medicine, Rochester, Minnesota. Department of Laboratory Medicine and reprogramming to AR independence represents an additional Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota. 7Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, resistance mechanism (5). Interestingly, the incidence of AR- New York, New York. 8Department of Urology, Mayo Clinic College of Medicine, independent tumor progression after castration and antiandrogen Rochester, Minnesota. 9Mayo Clinic Cancer Center, Mayo Clinic College of treatment has increased since the advent of enzalutamide and Medicine, Rochester, Minnesota. abiraterone use in the clinic, highlighting that prostate cancer Note: Supplementary data for this article are available at Clinical Cancer lineage plasticity is an increasingly important barrier to overcome Research Online (http://clincancerres.aacrjournals.org/). (6). Recent studies have identified a few key molecular events RB1 A.M. Blee, Y. He, and Y. Yang contributed equally to this article. involved in AR-independent tumor progression, such as / PTEN/TP53 loss, MYCN/AURKA amplification, and altered epi- Corresponding Authors: Haojie Huang, Department of Biochemistry and Molec- genetic regulators including EZH2 (7). However, the molecular ular Biology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-293-1712; Fax: 507-293-3071; E-mail: basis underlying prostate cancer lineage plasticity and antiandro- [email protected]; Liguo Wang, Department of Health Sciences gen resistance remains poorly understood due to extensive patient Research, Mayo Clinic College of Medicine, Rochester, MN 55905. E-mail: tumor heterogeneity and model limitations. [email protected]; and Wanhai Xu, Department of Urology, the Fourth PTEN loss frequently overlaps with TP53 mutation or loss in Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China. E-mail: drug-resistant, morphologically distinct, reprogrammed tumors [email protected] (8–11). A significant proportion of both primary and castration- doi: 10.1158/1078-0432.CCR-18-0653 resistant tumors with PTEN/TP53 alteration also have AR-depen- Ó2018 American Association for Cancer Research. dent, TMPRSS2 fusion–driven overexpression of the ETS family www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst May 29, 2018; DOI: 10.1158/1078-0432.CCR-18-0653 Blee et al. used within 6 months of thawing. No mycoplasma contamina- Translational Relevance tion was detected in these cell lines by testing with the Lookout Prostate cancer resistance to androgen deprivation and AR- Mycoplasma PCR Detection Kit (Sigma-Aldrich). Charcoal- targeted therapies remains a pressing clinical obstacle, partly stripped serum (CSS) was purchased from Thermo Fisher Scien- explained by lineage plasticity and transition to AR-indepen- tific-Gibco (#12676029). Enzalutamide was kindly provided by dent tumor types in response to these therapies. A compre- Medivation. LNCaP-RF cells were treated with 10 mmol/L of hensive understanding of genetic prostate tumor subtypes and enzalutamide for 72 hours unless otherwise noted. Palbociclib the unique response of each mutational subtype to AR-tar- (PD-0332991) was obtained from ApexBio. LNCaP-RF cells were geted therapies is necessary to develop new, subtype-specific treated with 1 mmol/L of palbociclib for 72 hours unless otherwise therapeutic strategies that overcome therapy-induced lineage noted. For combination treatment, LNCaP-RF cells were treated plasticity. Our results demonstrate that E-twenty-six transfor- with 10 mmol/L enzalutamide and 1 mmol/L palbociclib for mation specific (ETS)-related gene (ERG) prevents PTEN- and 72 hours. tumor protein 53 (TP53)-negative tumor cell lineage plasticity and antiandrogen resistance by blocking E2F1-mediated Cell transfection and lentivirus transduction expression of lineage switch genes. These findings also reveal For lentiviral shRNA or stable plasmid expression, HEK293T the efficacy of targeting retinoblastoma (RB)/E2F1 activity cells were transiently transfected with pTsin-HA-ERG FL, pTsin- with palbociclib in ERG-negative, PTEN/TP53-altered tumors. HA-ERG-T1-E4, pTsin-EV, pLKO-shNT, pLKO-shRB, pLKO- This study redefines the role of ERG in a specific tumor subtype shERG, pLKO-shPTEN, or pLKO-shE2F1 as indicated using Lipo- and may guide evaluation of the status of concomitant ERG fectamine 2000 (Thermo Fisher Scientific) following manufac- fusion, PTEN/TP53 alteration, and RB1 when selecting ther- turer's instructions. Virus-containing supernatant was collected apeutic strategies. 48 hours posttransfection and indicated cells were infected with virus-containing supernatant and 8 mg/mL polybrene. Selection was performed with 1.5 mg/mL puromycin. Sequences of gene- specific shRNAs are listed in Supplementary Table S1. Two shRNAs per gene were tested. transcription factor ERG (2–4). ERG alone has been shown to repress a neural gene expression signature (12) as well as partially rescue the AR pathway under PTEN loss conditions (13), but the Coimmunoprecipitation and Western blotting mechanistic role of ERG in the clinically relevant context of both Coimmunoprecipitation and subsequent Western blotting PTEN/TP53 alteration remains uncharacterized. was performed as described previously (15). The following Toaddressthesegapsinthefield, we generated a mouse antibodies were used: anti-ERG (ab92513, Abcam; CM421C, modelofprostatecancerthatencompassesPten deletion, Trp53 Biocare Medical), anti-PTEN (CST9559L, Cell Signaling Tech- mutation, and ERG overexpression. Notably, we revealed a nology), anti-p53 (sc126, Santa Cruz Biotechnology), anti-AR novel function of ERG to repress expression of a subset of cell (sc816, Santa Cruz Biotechnology), anti-NKX3.1 (NB100-1828, cycle–related genes and block RB hyperphosphorylation in Novus Biologicals), anti-RB (554136, BD Biosciences), anti- Pten/Trp53-altered, Rb1-intact tumors. As a result, ERG-positive, pRB S795 (CST9301S, Cell Signaling Technology), anti-SKP2 Pten/Trp53-altered tumors had minimal expression of E2F1 (32-3300, Life Technologies),
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