title: JARID1B is a luminal lineage-driving oncogene in breast cancer.
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.
authors.affiliation: 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.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: 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.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Hege G
authors.initials: HG
authors.lastname: Russnes
authors.affiliation: 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.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takagi
authors.affiliation: 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.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Peluffo
authors.affiliation: Five3 Genomics, Santa Cruz, CA 95060, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Vaske
authors.affiliation: Stanford Center for Cancer Systems Biology, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Oslo University Hospital, Radiumhospitalet, Oslo 0310, Norway.
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Moen Vollan
authors.affiliation: 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.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: 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.
authors.forename: Muhammad B
authors.initials: MB
authors.lastname: Ekram
authors.affiliation: 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.
authors.forename: Hanfei
authors.initials: H
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Carver
authors.affiliation: 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.
authors.forename: Mattia
authors.initials: M
authors.lastname: Zucca
authors.affiliation: Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Jianxing
authors.initials: J
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almendro
authors.affiliation: Thomson Reuters Healthcare & Science, Encinitas, CA 92024, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bessarabova
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Thomson Reuters Healthcare & Science, Encinitas, CA 92024, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikolsky
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: 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.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000076246:CCCTC-Binding Factor; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D006657:Histones; C530108:LY2109761; D009687:Nuclear Proteins; D011720:Pyrazoles; D011758:Pyrroles; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human