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Cancer Cell. 2014 Jun 16;25(6):762-77. doi: 10.1016/j.ccr.2014.04.024.

JARID1B is a luminal lineage-driving oncogene in breast cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard School of Public Health, Boston, MA 02115, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Oslo University Hospital, Radiumhospitalet, Oslo 0310, Norway.
4
Five3 Genomics, Santa Cruz, CA 95060, USA.
5
Stanford Center for Cancer Systems Biology, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Oslo University Hospital, Radiumhospitalet, Oslo 0310, Norway.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; School of Medicine, Sapporo Medical University, Sapporo 060-8556, Japan.
8
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; San Raffaele University, 20132 Milan, Italy.
11
Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
12
Thomson Reuters Healthcare & Science, Encinitas, CA 92024, USA.
13
Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
14
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard School of Public Health, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02141, USA.
15
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02141, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.

Abstract

Recurrent mutations in histone-modifying enzymes imply key roles in tumorigenesis, yet their functional relevance is largely unknown. Here, we show that JARID1B, encoding a histone H3 lysine 4 (H3K4) demethylase, is frequently amplified and overexpressed in luminal breast tumors and a somatic mutation in a basal-like breast cancer results in the gain of unique chromatin binding and luminal expression and splicing patterns. Downregulation of JARID1B in luminal cells induces basal genes expression and growth arrest, which is rescued by TGFβ pathway inhibitors. Integrated JARID1B chromatin binding, H3K4 methylation, and expression profiles suggest a key function for JARID1B in luminal cell-specific expression programs. High luminal JARID1B activity is associated with poor outcome in patients with hormone receptor-positive breast tumors.

PMID:
24937458
PMCID:
PMC4079039
DOI:
10.1016/j.ccr.2014.04.024
[Indexed for MEDLINE]
Free PMC Article

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