Journal
CANCER RESEARCH
Volume 77, Issue 4, Pages 1035-1046Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-2621
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Funding
- JP Sulzberger Columbia Genome Center
- Small-Animal Imaging Facility
- NIH/NCI grant [P30 CA013696, P30 CA008748]
- NIH [CA193442, CA182587]
- TJ Martell Foundation for Leukemia, Cancer and AIDS Research
- Bladder Cancer Advocacy Network
- Urology Care Foundation Research Scholars Program
- Dornier MedTech
- American Urological Association Foundation
- American Association for Cancer Research-Amgen Clinical and Translational Cancer Research Fellowship
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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 protein ITGB3BP (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. (C)2017 AACR.
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