title: The methyltransferase EZH2 is not required for mammary cancer development, although high EZH2 and low H3K27me3 correlate with poor prognosis of ER-positive breast cancers.
abstract: Enhancer of zeste homolog 2 (EZH2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and its demethylation is catalyzed by UTX. EZH2 levels are frequently elevated in breast cancer and have been proposed to control gene expression through regulating repressive H3K27me3 marks. However, it is not fully established whether breast cancers with different levels of H3K27me3, EZH2 and UTX exhibit different biological behaviors. Levels of H3K27me3, EZH2 and UTX and their prognostic significance were evaluated in 146 cases of breast cancer. H3K27me3 levels were higher in HER2-negative samples. EZH2 expression was higher in cancers that were LN+, size > 20mm, and with higher tumor grade and stage. Using a Cox regression model, H3K27me3 levels and EZH2 expression were identified as independent prognostic factors for overall survival for all the breast cancers studied as well as the ER-positive subgroup. The combination of low H3K27me3 and high EZH2 expression levels were significantly associated with shorter survival. UTX expression was not significantly associated with prognosis and there were no correlations between H3K27me3 levels and EZH2/UTX expression. To determine if EZH2 is required to establish H3K27me3 marks in mammary cancer, Brca1 and Ezh2 were deleted in mammary stem cells in mice. Brca1-deficient mammary cancers with unaltered H3K27me3 levels developed in the absence of EZH2, demonstrating that EZH2 is not a mandatory H3K27 methyltransferase in mammary neoplasia and providing genetic evidence for biological independence between H3K27me3 and EZH2 in this tissue.
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Health, Bethesda, Maryland.|Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Woo Kyun
authors.initials: WK
authors.lastname: Bae
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Health, Bethesda, Maryland.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Department of Pathology, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Ji Shin
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Pathology, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Young
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Ik-Joo
authors.initials: IJ
authors.lastname: Chung
authors.affiliation: Department of Surgery, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Park
authors.affiliation: Department of Surgery, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Jung Han
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Oncology and Medicine, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Furth
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism*; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; D011960:Receptors, Estrogen; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: EZH2; UTX; cancer; histone modification; prognosis