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 journalArticle

6 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 EZH2high population with enhanced invasion, mammosphere formation, and metastatic potential that exhibits marked sensitivity to EZH2 inhibition. Mechanistically, EZH2 inhibition differentiates EZH2high 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 EZH2high basal-like 1 and mesenchymal subtypes have exquisite sensitivity to EZH2 inhibition compared with the EZH2low luminal androgen receptor subtype. These preclinical findings provide a rationale for clinical development of EZH2 as a targeted therapy against TNBC metastasis. TNBC presents a clinical challenge because it exhibits a high incidence of metastatic recurrence. Yomtoubian et al. identify a highly metastatic basal-like subpopulation in the primary tumor that expresses elevated EZH2 levels. EZH2 inhibition induces luminal differentiation by derepressing GATA3, rendering tumors sensitive to endocrine therapy, and inhibiting 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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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