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EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based

Julian Puppe1,2,3, Mark Opdam4, Philip C Schouten4

  • 1Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. julian.puppe@uk-koeln.de.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 1, 2019
PubMed
Abstract

Insights

EZH2 is overexpressed in BRCA1-deficient breast cancers, identifying patients who benefit from platinum chemotherapy. EZH2 inhibition enhances platinum drug efficacy in BRCA1-deficient tumors.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • BRCA1-deficient breast cancers exhibit a distinct DNA copy-number signature and heightened sensitivity to DNA double-strand break (DSB) inducing agents.
  • EZH2 (Enhancer of Zeste Homolog 2) is a key epigenetic regulator implicated in various cancers.

Purpose of the Study:

  • To investigate EZH2 overexpression in human BRCA1-deficient breast tumors and its potential as a predictor of sensitivity to DSB-inducing drugs.
  • To evaluate if EZH2 inhibition can enhance the efficacy of cisplatin in BRCA1-deficient murine mammary tumors.

Main Methods:

  • Analyzed EZH2 expression in 497 breast cancers via IHC or RNA sequencing.
  • Classified tumors based on copy-number profiles (BRCA1-like or non-BRCA1-like) and assessed BRCA1 loss (mutation or promoter methylation).
  • Utilized a BRCA1-deficient mouse model to test combined EZH2 inhibition (GSK126) and cisplatin treatment.

Main Results:

  • Highest EZH2 expression was observed in BRCA1-associated tumors (mutation, methylation, or BRCA1-like status).
  • Patients with high EZH2 expression, regardless of BRCA1-like status, showed greater benefit from high-dose platinum-based chemotherapy.
  • Combined GSK126 and cisplatin treatment reduced cell proliferation and improved survival in BRCA1-deficient mice compared to single agents.

Conclusions:

  • EZH2 is significantly upregulated in BRCA1-deficient breast cancers.
  • EZH2 overexpression identifies breast cancer patients who benefit from intensified platinum-based chemotherapy, independent of BRCA1-like status.
  • EZH2 inhibition potentiates the antitumor effects of platinum drugs in BRCA1-deficient breast tumors in vivo.

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