Targeting the MLL complex in castration-resistant prostate cancer.
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Authors
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Malik, Rohit1
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Khan, Amjad P1
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Asangani, Irfan A1
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Cieślik, Marcin1
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Prensner, John R1
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Wang, Xiaoju1
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Iyer, Matthew K1
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Jiang, Xia1
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Borkin, Dmitry2
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Escara-Wilke, June1
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Stender, Rachell1
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Wu, Yi-Mi1
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Niknafs, Yashar S3
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Jing, Xiaojun1
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Qiao, Yuanyuan1
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Palanisamy, Nallasivam4
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Kunju, Lakshmi P5
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Krishnamurthy, Pranathi M3
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Yocum, Anastasia K3
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Mellacheruvu, Dattatreya6
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Nesvizhskii, Alexey I7
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Cao, Xuhong8
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Dhanasekaran, Saravana M1
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Feng, Felix Y9
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Grembecka, Jolanta2
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Cierpicki, Tomasz2
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Chinnaiyan, Arul M5
And 7 more
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1
1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
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2
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
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3
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
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4
1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Urology, Henry Ford Health System, Detroit, Michigan, USA.
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5
1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan,
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6
1] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
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7
1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Computational Medicine and Bioinformatics, University of Mic
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8
1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA.
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9
1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
- Type
- Published Article
- Journal
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Nature medicine
- Publication Date
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March 2015
- Volume
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21
- Issue
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4
- Pages
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344–352
- Identifiers
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DOI: 10.1038/nm.3830
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PMID: 25822367
- Source
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Medline
- License
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Unknown
Abstract
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
This record was last updated on 07/07/2017 and may not reflect the most current and accurate biomedical/scientific data available from NLM.
The corresponding record at NLM can be accessed at
https://www.ncbi.nlm.nih.gov/pubmed/25822367
