BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A

Breast Cancer Res. 2009;11(4):R63. doi: 10.1186/bcr2354. Epub 2009 Aug 26.


Introduction: Treatment of breast cancer is becoming more individualized with the recognition of tumor subgroups that respond differently to available therapies. Breast cancer 1 gene (BRCA1)-deficient tumors are usually of the basal subtype and associated with poor survival rates, highlighting the need for more effective therapy.

Methods: We investigated a mouse model that closely mimics breast cancer arising in BRCA1-mutation carriers to better understand the molecular mechanism of tumor progression and tested whether targeting of the Polycomb-group protein EZH2 would be a putative therapy for BRCA1-deficient tumors.

Results: Gene expression analysis demonstrated that EZH2 is overexpressed in BRCA1-deficient mouse mammary tumors. By immunohistochemistry we show that an increase in EZH2 protein levels is also evident in tumors from BRCA1-mutation carriers. EZH2 is responsible for repression of genes driving differentiation and could thus be involved in the undifferentiated phenotype of these tumors. Importantly, we show that BRCA1-deficient cancer cells are selectively dependent on their elevated EZH2 levels. In addition, a chemical inhibitor of EZH2, 3-deazaneplanocin A (DZNep), is about 20-fold more effective in killing BRCA1-deficient cells compared to BRCA1-proficient mammary tumor cells.

Conclusions: We demonstrate by specific knock-down experiments that EZH2 overexpression is functionally relevant in BRCA1-deficient breast cancer cells. The effectiveness of a small molecule inhibitor indicates that EZH2 is a druggable target. The overexpression of EZH2 in all basal-like breast cancers warrants further investigation of the potential for targeting the genetic make-up of this particular breast cancer type.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Animals
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / genetics
  • BRCA1 Protein / physiology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • DNA Repair / genetics
  • Drug Delivery Systems
  • Enhancer of Zeste Homolog 2 Protein
  • Female
  • Gene Knockdown Techniques
  • Genes, BRCA1*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase / biosynthesis
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / physiology*
  • Humans
  • Mice
  • Mutation
  • Polycomb Repressive Complex 2
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • RNA, Small Interfering / pharmacology
  • Recombinant Fusion Proteins / physiology


  • BRCA1 Protein
  • BRCA1 protein, human
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • 3-deazaneplanocin
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2
  • Adenosine