Senologie - Zeitschrift für Mammadiagnostik und -therapie 2015; 12 - A115
DOI: 10.1055/s-0035-1550556

EZH2 is overexpressed in breast tumors with a BRCA1-like DNA copy number profile

J Puppe 1, M Opdam 2, P Schouten 2, P Mallmann 3, S Rodenhuis 4, M Hauptmann 5, R Schmutzler 6, S Linn 2, J Jonkers 2
  • 1University Hospital Cologne, Department of Obstetrics and Gynecology, Cologne, Deutschland
  • 2The Niederlande Cancer Institute, Division of Molecular Pathology, Amsterdam, Niederlande
  • 3University Hospital Cologne, Department of Obstetrics and Gynecology, Cologne, Niederlande
  • 4The Niederlande Cancer Institute, Department of Medical Oncology, Amsterdam, Niederlande
  • 5The Niederlande Cancer Institute, Department of Epidemiology and Biostatistics, Amsterdam, Niederlande
  • 6Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Niederlande

Purpose: The polycomb group protein EZH2 is an epigenetic repressor through its trimethylase activity of H3K27me3 and overexpression of EZH2 is associated with aggressive types of breast cancer. We previously reported that breast tumors deriving from a BRCA1-deficient mouse model show high levels of EZH2. Human BRCA1-mutated breast tumors carry a specific DNA copy-number signature („BRCA1-like“) which is also found in tumors with a loss of BRCA1 function by other mechanism such as BRCA1-promoter methylation. Here, we explored whether EZH2 is overexpressed in human BRCA1-like breast tumors.

Patients and methods: In our study we analyzed the abundance of EZH2 and H3K27me3 expression using immunohistochemistry in a cohort of 400 breast cancer patients. We classified copy-number profiles by array comparative genomic hybridization (aCGH) to be BRCA1-like or non-BRCA1-like in 160 patients and examined its association with EZH2 and H3K27me3 expression.

Results: 266 tumors were considered to be EZH2 positive whereas 304 tumors were positive for H3K27me3. EZH2 expression was significantly higher in triple-negative and HER2+ breast tumors compared to hormone receptor positive breast tumors. No significant associations were found for H3K27me3. Out of the tumors classified by aCGH 36 samples show a BRCA1-like profile whereas 124 were non-BRCA1-like. The group of BRCA1-like tumors included 14 samples with a BRCA1-promoter methylation and 6 samples with BRCA1-mutation. The highest EZH2 expression was found in tumors classified as BRCA1-like when compared to non-BRCA1-like breast tumors. Among triple-negative breast tumors higher levels of EZH2 and H3K27me3 were found in the subgroup of BRCA1-like breast tumors.

Conclusion: Our findings demonstrate that EZH2 is significantly higher expressed in breast tumors with a BRCA1-like DNA copy number profile indicating that EZH2 overexpression is not restricted to BRCA1-mutation status. Therefore, EZH2 should be further examined as prognostic biomarker and potential target for breast tumors identified by the BRCA1-like classifier.