EZH2 promotes a bi-lineage identity in basal-like breast cancer cells

R. Z. Granit, Y. Gabai, T. Hadar, Y. Karamansha, L. Liberman, I. Waldhorn, I. Gat-Viks, A. Regev, B. Maly, M. Darash-Yahana, T. Peretz, I. Ben-Porath*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageAmerican English
Pages (from-to)3886-3895
Number of pages10
JournalOncogene
Volume32
Issue number33
DOIs
StatePublished - 15 Aug 2013

Bibliographical note

Funding Information:
We thank Eli Pikarsky, Yuval Dor and Yehudit Bergman for critical reviewing of the manuscript, Marius Wernig for the Fip-EZH2 construct, Alex Roesch and Meenhard Herlyn for the pLU-JARID1Bp-GFP-BlastR construct and Sabine Werner for the CK14 promoter plasmid. We thank Norma E. Kidess–Bassir for histological support. This study was supported by the Israel Science Foundation (Grant 1560/07), the Israel Cancer Association, the Israel Cancer Research Foundation, and the Joint Research Fund IMRIC-Hadassah.

Keywords

  • EZH2
  • GATA3
  • Polycomb
  • basal-like
  • breast cancer
  • differentiation

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