title: ARF Confers a Context-Dependent Response to Chemotherapy in Muscle-Invasive Bladder Cancer.
abstract: Muscle-invasive bladder cancer (MIBC) generally responds poorly to treatment and tends to exhibit significant mortality. Here we show that expression of the tumor suppressor p14ARF(ARF) is upregulated in aggressive subtypes of MIBC. Accumulation of ARF in the nucleolus is associated with poor outcome and attenuated response to chemotherapy. In both genetically engineered mouse models and murine xenograft models of human MIBC, we demonstrate that tumors expressing ARF failed to respond to treatment with the platinum-based chemotherapy agent cisplatin. Resistance was mediated in part by the integrin-binding proteinITGB3BP(CENPR) and reflected ARF-dependent impairment of protein translation, which was exaggerated by drug treatment. Overall, our results highlight a context-dependent role for ARF in modulating the drug response of bladder cancer.Cancer Res; 77(4); 1035-46. ©2017 AACR.
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York.|Department of Urology, Columbia University Medical Center, New York, New York.
authors.forename: Tomasz B
authors.initials: TB
authors.lastname: Owczarek
authors.affiliation: Department of Urology, Columbia University Medical Center, New York, New York.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Human Oncology and Pathogenesis, Memorial Sloan-Kettering Cancer Center, New York, New York.|Weill Cornell Graduate School, Cornell University, New York, New York.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ramirez
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York.|Department of Urology, Columbia University Medical Center, New York, New York.
authors.forename: Lijie
authors.initials: L
authors.lastname: Rong
authors.affiliation: Department of Urology, Columbia University Medical Center, New York, New York.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Puzio-Kuter
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.|Weill Medical College, Cornell University, New York, New York.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Min Yuen
authors.initials: MY
authors.lastname: Teo
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Vega
authors.affiliation: Department of Urology, Columbia University Medical Center, New York, New York.
authors.forename: Jingqiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Department of Statistics, Columbia University, New York, New York.
authors.forename: Tian
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Human Oncology and Pathogenesis, Memorial Sloan-Kettering Cancer Center, New York, New York.|Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.|Weill Medical College, Cornell University, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Hikmat A
authors.initials: HA
authors.lastname: Al-Ahmadie
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York. cabateshen@columbia.edu.|Department of Urology, Columbia University Medical Center, New York, New York.|Department of Systems Biology, Columbia University Medical Center, New York, New York.|Department of Pathology & Cell Biology, Columbia University Medical Center, New York, New York.|Institute of Cancer Genetics, Columbia University Medical Center, New York, New York.|Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors.forename: Cory
authors.initials: C
authors.lastname: Abate-Shen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000032:analysis / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C403295:ITGB3BP protein, human; D009687:Nuclear Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin