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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Cell-cycle coupled expansion of AR activity promotes cancer progression
Oncogene, v 36(12), pp 1655-1668
26 Sep 2016
PMID: 27669432
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle (“Cell Cycle Common”), versus those that were specifically enriched in a subset of cell cycle phases (“Phase Restricted”). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide-desaturase 1 (DEGS1) was identified as an AR regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention, and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.
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- Title
- Cell-cycle coupled expansion of AR activity promotes cancer progression
- Creators
- Christopher McNair - Kimmel Cancer CenterAlfonso Urbanucci - Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospitals, Oslo, NorwayClay E.S. Comstock - Kimmel Cancer CenterMichael A. Augello - Kimmel Cancer CenterJonathan F. Goodwin - Kimmel Cancer CenterRosalind Launchbury - Cancer Research UKShuang Zhao - University of Michigan–Ann ArborMathew J. Schiewer - Sidney Kimmel Cancer Center, Thomas Jefferson Univ., Philadelphia, PA, 19107 Michigan Center for Translational Pathology, Univ. of Michigan, Ann Arbor, MI, 48109 GenomeDx Biosciences, San Diego, CA, 92121 Cambridge Research Institute, Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE, UK Mayo Clinic College of Medicine, Rochester, MN, 55905 Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Univ. of Oslo and Oslo Univ. Hospitals, N-0349 Dan L. Duncan Cancer Center and Dept of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA Ohio State Univ. College of Medicine, Columbus, OH 43210 Dept of Molecular Oncology, Institute for Cancer Research, Oslo Univ. Hospitals, N-0456, Oslo, Norway Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Queen’s University Belfast, Belfast, BT7 9AE, UK Dept of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143Adam Ertel - Sidney Kimmel Cancer CenterJeffrey Karnes - Sidney Kimmel Cancer Center, Thomas Jefferson Univ., Philadelphia, PA, 19107 Michigan Center for Translational Pathology, Univ. of Michigan, Ann Arbor, MI, 48109 GenomeDx Biosciences, San Diego, CA, 92121 Cambridge Research Institute, Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE, UK Mayo Clinic College of Medicine, Rochester, MN, 55905 Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Univ. of Oslo and Oslo Univ. Hospitals, N-0349 Dan L. Duncan Cancer Center and Dept of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA Ohio State Univ. College of Medicine, Columbus, OH 43210 Dept of Molecular Oncology, Institute for Cancer Research, Oslo Univ. Hospitals, N-0456, Oslo, Norway Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Queen’s University Belfast, Belfast, BT7 9AE, UK Dept of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143Elai Davicioni - GenomeDx Biosciences, San Diego, CA, USA.Liguo Wang - Sidney Kimmel Cancer Center, Thomas Jefferson Univ., Philadelphia, PA, 19107 Michigan Center for Translational Pathology, Univ. of Michigan, Ann Arbor, MI, 48109 GenomeDx Biosciences, San Diego, CA, 92121 Cambridge Research Institute, Cancer Research UK Cambridge Institute, University of Cambridge, CB2 0RE, UK Mayo Clinic College of Medicine, Rochester, MN, 55905 Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Univ. of Oslo and Oslo Univ. Hospitals, N-0349 Dan L. Duncan Cancer Center and Dept of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA Ohio State Univ. College of Medicine, Columbus, OH 43210 Dept of Molecular Oncology, Institute for Cancer Research, Oslo Univ. Hospitals, N-0456, Oslo, Norway Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Queen’s University Belfast, Belfast, BT7 9AE, UK Dept of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143Qianben Wang - The Ohio State UniversityIan G. Mills - Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospitals, Oslo, NorwayFelix Y. Feng - UCSF Helen Diller Family Comprehensive Cancer CenterWei Li - Baylor College of MedicineJason S. Carroll - Cancer Research UKKaren E. Knudsen - Kimmel Cancer Center
- Publication Details
- Oncogene, v 36(12), pp 1655-1668
- Publisher
- Springer Nature
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000397460600005
- Scopus ID
- 2-s2.0-84988736441
- Other Identifier
- 991019176795504721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology
- Genetics & Heredity
- Oncology