Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes

Molecular Oncology - Tập 6 - Trang 494-506 - 2012
Karolina Holm1,2, Dorthe Grabau3, Kristina Lövgren1, Steina Aradottir1, Sofia Gruvberger-Saal1,2, Jillian Howlin1,2, Lao H. Saal1,2, Stephen P. Ethier4, Pär-Ola Bendahl1, Olle Stål5, Per Malmström1, Mårten Fernö1, Lisa Rydén6, Cecilia Hegardt1,2, Åke Borg1,2, Markus Ringnér1,2
1Department of Oncology, Clinical Sciences, Lund University, Skåne University Hospital, SE-221 85 Lund, Sweden
2CREATE Health Strategic Centre for Translational Cancer Research, Lund University, SE-221 84 Lund, Sweden
3Department of Clinical Pathology, Laboratory Medicine, Skåne University Hospital, SE-221 85 Lund, Sweden
4Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
5Department of Clinical and Experimental Medicine, Division of Oncology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden
6Department of Surgery, Clinical Sciences, Lund University, Skåne University Hospital, SE-221 85 Lund, Sweden

Tóm tắt

Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and well‐characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal‐like, luminal A, luminal B, HER2‐enriched and normal‐like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2−/Ki67low, ER+/HER2−/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal‐like, triple negative and HER2‐enriched tumors, and high H3K27me3 in luminal A, HER2‐enriched and normal‐like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal‐like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease‐free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.

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Molecular Oncology

Tập 6

494-506

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