JARID1B is a luminal lineage-driving oncogene in breast cancer

Shoji Yamamoto; Zhenhua Wu; Hege G Russnes; Shinji Takagi; Guillermo Peluffo; Charles Vaske; Xi Zhao; Hans Kristian Moen Vollan; Reo Maruyama; Muhammad B Ekram; Hanfei Sun; Jee Hyun Kim; Kristopher Carver; Mattia Zucca; Jianxing Feng; Vanessa Almendro; Marina Bessarabova; Oscar M Rueda; Yuri Nikolsky; Carlos Caldas; X Shirley Liu; Kornelia Polyak

doi:10.1016/j.ccr.2014.04.024

JARID1B is a luminal lineage-driving oncogene in breast cancer

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

Authors

Shoji Yamamoto¹, Zhenhua Wu², Hege G Russnes³, Shinji Takagi¹, Guillermo Peluffo¹, Charles Vaske⁴, Xi Zhao⁵, Hans Kristian Moen Vollan⁶, Reo Maruyama⁷, Muhammad B Ekram¹, Hanfei Sun⁸, Jee Hyun Kim⁹, Kristopher Carver¹, Mattia Zucca¹⁰, Jianxing Feng¹¹, Vanessa Almendro¹, Marina Bessarabova¹², Oscar M Rueda¹³, Yuri Nikolsky¹², Carlos Caldas¹³, X Shirley Liu¹⁴, Kornelia Polyak¹⁵

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
CCCTC-Binding Factor
Cell Growth Processes / genetics
Cell Line, Tumor
Cell Lineage
Female
Gene Amplification
Gene Expression Regulation, Neoplastic
Histones / genetics
Histones / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases / genetics*
Jumonji Domain-Containing Histone Demethylases / metabolism
MCF-7 Cells
Mutation
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Oncogenes*
Promoter Regions, Genetic
Pyrazoles / pharmacology
Pyrroles / pharmacology
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
Repressor Proteins / genetics*
Repressor Proteins / metabolism
Transfection
Transforming Growth Factor beta / metabolism

Substances

CCCTC-Binding Factor
CTCF protein, human
Histones
LY2109761
Nuclear Proteins
Pyrazoles
Pyrroles
RNA, Small Interfering
Repressor Proteins
Transforming Growth Factor beta
Jumonji Domain-Containing Histone Demethylases
KDM5B protein, human

Associated data

GEO/GSE19399
GEO/GSE46073

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding