title: EZH2 promotes a bi-lineage identity in basal-like breast cancer cells.
abstract: The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a ‘bi-lineage’ differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony-formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal-progenitor gene expression. GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute for Medical Research – Israel-Canada, Hadassah School of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: R Z
authors.initials: RZ
authors.lastname: Granit
authors.forename: Y
authors.initials: Y
authors.lastname: Gabai
authors.forename: T
authors.initials: T
authors.lastname: Hadar
authors.forename: Y
authors.initials: Y
authors.lastname: Karamansha
authors.forename: L
authors.initials: L
authors.lastname: Liberman
authors.forename: I
authors.initials: I
authors.lastname: Waldhorn
authors.forename: I
authors.initials: I
authors.lastname: Gat-Viks
authors.forename: A
authors.initials: A
authors.lastname: Regev
authors.forename: B
authors.initials: B
authors.lastname: Maly
authors.forename: M
authors.initials: M
authors.lastname: Darash-Yahana
authors.forename: T
authors.initials: T
authors.lastname: Peretz
authors.forename: I
authors.initials: I
authors.lastname: Ben-Porath
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D014183:Transplantation, Heterologous
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2