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

Abstract

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.

• Authors: Julian Puppe, Rinske Drost, Xiaoling Liu, Simon A Joosse, Bastiaan Evers, Paulien Cornelissen-Steijger, Petra Nederlof, Qiang Yu, Jos Jonkers, Maarten van Lohuizen, Alexandra M Pietersen
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 11 Issue 4 Pg. R63 ( 2009) ISSN: 1465-542X [Electronic] England
• PMID: 19709408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Animals
• BRCA1 Protein (deficiency, genetics, physiology)
• Breast Neoplasms (genetics, pathology)
• Cell Line, Tumor (drug effects, 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, biosynthesis, genetics, physiology)
• Humans
• Mice
• Mutation
• Polycomb Repressive Complex 2
• RNA, Messenger (biosynthesis)
• RNA, Neoplasm (biosynthesis)
• RNA, Small Interfering (pharmacology)
• Recombinant Fusion Proteins (physiology)