JARID1B is a luminal lineage-driving oncogene in breast cancer

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. •Somatic genetic alterations of JARID1B in breast cancer•Importance of JARID1B for luminal gene expression programs•Missense mutation in JARID1B leads to gain of luminal genes expression•High luminal JARID1B activity is associated with poor outcome in ER⁺ tumors. Yamamoto etal. show that histone demethylase JARID1B drives luminal programs in breast cancer. JARID1B alterations are frequent in luminal breast tumors, and somatic mutation is found in basal-like breast cancer expressing luminal genes. High JARID1B activity is associated with poor outcome in ER⁺ breast cancer.