Ding L, Erdmann C, Chinnaiyan AM, Merajver SD, Kleer CG.. Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 66: 4095-4099

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
Cancer Research (Impact Factor: 9.33). 05/2006; 66(8):4095-9. DOI: 10.1158/0008-5472.CAN-05-4300
Source: PubMed


The discovery of molecular markers to detect the precancerous state would have profound implications in the prevention of breast cancer. We report that the expression of the Polycomb group protein EZH2 increases in histologically normal breast epithelium with higher risk of developing cancer. We identify EZH2 as a potential marker for detecting preneoplastic lesions of the breast in vivo and as a possible target for preventative intervention.

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Available from: Arul M Chinnaiyan, Sep 07, 2015
    • "The mechanistic basis of CIMP remains unsettled . The CIMP phenotype and altered methyl- transferase expression often co-exist in tumorigenesis, sharing early appearance (Ding et al., 2006; Ibrahim et al., 2011), tissue-specificity (Joensuu et al., 2008; this study), role in tumor progression (Ibrahim et al., 2011; this study in regard to endometrial hyperplasias), and contribution to the prognosis of CRC and EC (Bachmann et al., 2006; Issa, 2008; Fluge et al., 2009; Benard et al., 2014). Such observations imply that the processes are likely to be linked, although their relationship may not be straightforward. "
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    ABSTRACT: Molecular mechanisms underlying coordinated hypermethylation of multiple CpG islands in cancer remain unclear and studies of methyltransferase enzymes have arrived at conflicting results. We focused on DNMT1 and DNMT3B, DNA methyltransferases responsible for (de novo) methylation, and EZH2, histone (H3K27) methyltransferase, and examined their roles in tumor suppressor gene (TSG) methylation patterns we have previously established in sporadic and familial cancers. Our investigation comprised 165 tumors, stratified by tissue of origin (117 colorectal and 48 endometrial carcinomas) and sporadic vs. familial disease (57 sporadic vs. 60 familial, mainly Lynch syndrome, colorectal carcinomas). By immunohistochemical evaluation, EZH2 protein expression was associated with a TSG methylator phenotype. DNMT1, DNMT3B, and EZH2 were expressed at significantly higher levels in tumor vs. normal tissues. DNMT1 and EZH2 expression were positively correlated and higher in microsatellite-unstable vs. microsatellite-stable tumors, whether sporadic or hereditary. Ki-67 expression mirrored the same pattern. Promoter methylation of the methyltransferase genes themselves was addressed as a possible cause behind their altered expression. While DNMT1 or EZH2 did not show differential methylation between normal and tumor tissues, DNMT3B analysis corroborated the regulatory role of a distal promoter region. Our study shows that methyltransferase expression in cancer depends on the tissue of origin, microsatellite-instability status, cellular proliferation, and-in the case of DNMT3B-promoter methylation of the respective gene. Translation of methyltransferase expression into DNA methylation appears complex as suggested by the fact that except for EZH2, no clear association between methyltransferase protein expression and TSG methylation was observed. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 08/2015; 54(12). DOI:10.1002/gcc.22289 · 4.04 Impact Factor
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    • "For example, in breast cancer cells transfected with siRNA against EZH2 (siEZH2), there was decreased cell and tumor growth, G 0 /G 1 to S phase cell cycle arrest, and induction of apoptosis, and this 1064 ZBTB4 Regulates EZH2 Expression in Breast Cancer Yang et al. Neoplasia Vol. 16, No. 12, 2014 was accompanied by alterations in histone methylation status [32] [33] [34]. Similar results were observed in other cancer cell types with some differences with respect to siEZH2-dependent inhibition of G 0 /G 1 to S phase progression in breast cancer cells vs. G 2 /M arrest in transformed fibroblasts [35]. "
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    ABSTRACT: ZBTB4 is a transcriptional repressor and examination of publically-available microarray data sets demonstrated an inverse relationship in the prognostic value and expression of ZBTB4 and the histone methyltransferase EZH2 in tumors from breast cancer patients. The possibility of functional interactions between EZH2 and ZBTB4 was investigated in breast cancer cells and the results showed that EZH2 is directly suppressed by ZBTB4 which in turn is regulated (suppressed) by miR-106b and other paralogues from the miR-17-92, miR-106b-25 and miR-106a-363 clusters that are highly expressed in breast and other tumors. ZBTB4 also acts a suppressor of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4, and RNA interference studies show that Sp proteins are required for EZH2 expression. The prediction analysis results from breast cancer patient array data sets confirm an association of Sp1-dependent EZH2 gene signature with decreased survival of breast cancer patients. Disruption of oncogenic miR-ZBTB4 signaling axis by anticancer agent such as betulinic acid that induce down-regulation of Sp proteins in breast cancer cells resulted in inhibition of tumor growth and colonization of breast cancer cells in a mouse model. Thus, EZH2 is reciprocally regulated by a novel signaling network consisting of Sp proteins, oncogenic miRs and ZBTB4, and modulation of this gene network is a novel therapeutic approach for treatment of breast cancer and possibly other cancers. Published by Elsevier Inc.
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    • "In breast cancer, PcG proteins, especially EZH2, Bmi-1, and SUZ12, are significantly overexpressed even at the very earliest stages of neoplastic transformation[165],[166]. The expression of EZH2 is low or absent in morphologically normal lobules, whereas EZH2 expression progressively increases with increasing severity of epithelial atypias[167]. "
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