1. JARID1B is a luminal lineage-driving oncogene in breast cancer
- Author
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Charles J. Vaske, Oscar M. Rueda, Zhenhua Wu, Muhammad B. Ekram, Marina Bessarabova, Shoji Yamamoto, Hans Kristian Moen Vollan, Hege G. Russnes, Shinji Takagi, Jianxing Feng, Yuri Nikolsky, Kristopher Carver, Kornelia Polyak, X. Shirley Liu, Jee Hyun Kim, Guillermo Peluffo, Carlos Caldas, Reo Maruyama, Hanfei Sun, Mattia Zucca, Vanessa Almendro, and Xi Zhao
- Subjects
Cancer Research ,CCCTC-Binding Factor ,Jumonji Domain-Containing Histone Demethylases ,Breast Neoplasms ,Cell Growth Processes ,medicine.disease_cause ,Transfection ,Article ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Transforming Growth Factor beta ,Cell Line, Tumor ,medicine ,Humans ,Cell Lineage ,Pyrroles ,RNA, Small Interfering ,Promoter Regions, Genetic ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,biology ,Oncogene ,Chromatin binding ,Gene Amplification ,Nuclear Proteins ,Cell Biology ,Oncogenes ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,Histone ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Cancer research ,MCF-7 Cells ,Demethylase ,Pyrazoles ,Female ,JARID1B ,Carcinogenesis - Abstract
SummaryRecurrent 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.
- Published
- 2014