Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer

Shira Yomtoubian, Sharrell B. Lee, Akanksha Verma, Franco Izzo, Geoffrey Markowitz, Hyejin Choi, Leandro Cerchietti, Linda Vahdat, Kristy A. Brown, Eleni Andreopoulou, Olivier Elemento, Jenny Chang, Giorgio Inghirami, Dingcheng Gao, Seongho Ryu, Vivek Mittal

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Epigenetic changes are increasingly being appreciated as key events in breast cancer progression. However, breast cancer subtype-specific epigenetic regulation remains poorly investigated. Here we report that EZH2 is a leading candidate of epigenetic modulators associated with the TNBC subtype and that it predicts poor overall survival in TNBC patients. We demonstrate that specific pharmacological or genetic inhibition of EZH2 catalytic activity impairs distant metastasis. We further define a specific EZH2 high population with enhanced invasion, mammosphere formation, and metastatic potential that exhibits marked sensitivity to EZH2 inhibition. Mechanistically, EZH2 inhibition differentiates EZH2 high basal cells to a luminal-like phenotype by derepressing GATA3 and renders them sensitive to endocrine therapy. Furthermore, dissection of human TNBC heterogeneity shows that EZH2 high basal-like 1 and mesenchymal subtypes have exquisite sensitivity to EZH2 inhibition compared with the EZH2 low luminal androgen receptor subtype. These preclinical findings provide a rationale for clinical development of EZH2 as a targeted therapy against TNBC metastasis.

Original languageEnglish (US)
Pages (from-to)755-770.e6
JournalCell Reports
Volume30
Issue number3
DOIs
StatePublished - Jan 21 2020

Keywords

  • EZH2
  • GATA3
  • breast cancer
  • circulating tumor cells
  • differentiation
  • epigenetics
  • metastasis
  • Cell Proliferation
  • Octamer Transcription Factor-3/metabolism
  • SOXB1 Transcription Factors/metabolism
  • Epigenesis, Genetic
  • Humans
  • Cell Compartmentation
  • Neoplasm Metastasis
  • Base Sequence
  • Female
  • Cell Differentiation
  • Mutant Proteins/metabolism
  • Biocatalysis
  • Neoplasm Invasiveness
  • Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors
  • Mice, SCID
  • Disease Progression
  • GATA3 Transcription Factor/metabolism
  • Phenotype
  • Animals
  • Cell Line, Tumor
  • Mice, Inbred BALB C
  • Triple Negative Breast Neoplasms/genetics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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