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.

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