title: Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes.
abstract: 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.
authors: Department of Oncology, Clinical Sciences, Lund University, Skåne University Hospital, SE-221 85 Lund, Sweden. karolina.holm@med.lu.se
authors: Karolina
authors: K
authors: Holm
authors: Dorthe
authors: D
authors: Grabau
authors: Kristina
authors: K
authors: Lövgren
authors: Steina
authors: S
authors: Aradottir
authors: Sofia
authors: S
authors: Gruvberger-Saal
authors: Jillian
authors: J
authors: Howlin
authors: Lao H
authors: LH
authors: Saal
authors: Stephen P
authors: SP
authors: Ethier
authors: Pär-Ola
authors: PO
authors: Bendahl
authors: Olle
authors: O
authors: Stål
authors: Per
authors: P
authors: Malmström
authors: Mårten
authors: M
authors: Fernö
authors: Lisa
authors: L
authors: Rydén
authors: Cecilia
authors: C
authors: Hegardt
authors: Åke
authors: Å
authors: Borg
authors: Markus
authors: M
authors: Ringnér
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008745:Methylation; D009154:Mutation; D063151:Polycomb Repressive Complex 2 / Q000032:analysis* / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2