Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Oct;54(10):1172-80.
doi: 10.1002/mc.22188. Epub 2014 Jul 7.

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

Woo Kyun Bae  1   2 , Kyung Hyun Yoo  1 , Ji Shin Lee  3 , Young Kim  3 , Ik-Joo Chung  2 , Min Ho Park  4 , Jung Han Yoon  4 , Priscilla A Furth  5 , Lothar Hennighausen  1
Affiliations

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

Woo Kyun Bae et al. Mol Carcinog. 2015 Oct.

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.

Keywords: EZH2; UTX; cancer; histone modification; prognosis.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Immunohistochemical staining of breast tumors for H3K27me3, EZH2 and UTX. Shown are representative examples of low and high expression, respectively.
Figure 2
Figure 2
Kaplan-Meier survival curves based on abundance of H3K27me3 and EZH2. Overall survival plots stratified by high or low expression of H3K27me3 and EZH2 in all cases (A, B, C). Overall survival plots stratified by high or low expression of H3K27me3 and EZH2 in ER-positive cancers (D, E, F).
Figure 3
Figure 3
Mammary epithelium-specific Brca1 inhibition (Ezh2+/+Brca1f/f;MMTV-CreADp53+/−) induced mammary tumors in mice at 32 weeks. Representative photographs depict H&E (×400) staining and EZH2 and H3K27m3 immunofluorescence of cancer tissue (×800) (row A), and adjacent mammary tissue (×800) (row B).
Figure 4
Figure 4
Mammary-specific loss of Ezh2 and Brca1 (Ezh2f/fBrca1f/f;MMTV-CreAp53+/−) in mice induced multiple different tumors at 21 weeks. Representative photographs depict H&E (X400) staining and EZH2 and H3K27m3 immunofluorescence of cancer tissue (X800) (row A) and adjacent mammary tissue (X800) (row B).
Figure 5
Figure 5
Mammary-specific loss of Ezh2 and Brca1 (DKO, Ezh2f/fBrca1f/f;MMTV-CreAp53+/−) in mice induced higher expression of ER compared to Brca1 inhibition in the presence of intact EZH2 (Brca1 KO, Ezh2+/+Brca1f/f;MMTV-CreAp53+/−). Representative photographs depict ER immunofluorescence of cancer tissue (X400) (row A) and adjacent mammary tissue (X400) (row B).
See this image and copyright information in PMC

References

    1. Ko SS. Chronological changing patterns of clinical characteristics of Korean breast cancer patients during 10 years (1996-2006) using nationwide breast cancer registration on-line program: biannual update. J Surg Oncol. 2008;98(5):318–323. - PubMed
    1. Khan SN, Jankowska AM, Mahfouz R, et al. Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies. Leukemia. 2013;27(6):1301–1309. - PubMed
    1. Piunti A, Pasini D. Epigenetic factors in cancer development: polycomb group proteins. Future Oncol. 2011;7(1):57–75. - PubMed
    1. Laible G, Wolf A, Dorn R, et al. Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. EMBO J. 1997;16(11):3219–3232. - PMC - PubMed
    1. Sauvageau M, Sauvageau G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 2010;7(3):299–313. - PMC - PubMed

Publication types

MeSH terms