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Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
Cancer Research (Impact Factor: 9.28). 05/2006; 66(8):4095-9. DOI: 10.1158/0008-5472.CAN-05-4300
Source: PubMed

ABSTRACT 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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    • "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.
    Neoplasia (New York, N.Y.) 12/2014; 16(12):1059-69. DOI:10.1016/j.neo.2014.09.011 · 5.40 Impact Factor
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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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    ABSTRACT: During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
    Ai zheng = Aizheng = Chinese journal of cancer 07/2013; 33(2). DOI:10.5732/cjc.013.10040
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    • "EZH2 levels were elevated in patients with invasive breast carcinoma relative to normal or atypical hyperplasia. Notably, increased expression was already observed in ductal carcinoma in situ (DCIS), a precursor of invasive carcinoma 21. "
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    ABSTRACT: Histone modifications are thought to control the regulation of genetic programs in normal physiology and cancer. Methylation (mono-, di-, and tri-methylation) on histone H3 lysine (K) 27 induces transcriptional repression, and thereby participates in controlling gene expression patterns. Enhancer of zeste (EZH) 2, a methyltransferase and component of the polycomb repressive complex 2 (PRC2), plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark. Abnormal EZH2 expression has been associated with various cancers including breast cancer. Here, we discuss the contribution of EZH2 and the PRC2 complex in controlling the H3K27 methylation status and subsequent consequences on genomic instability and the cell cycle in breast cancer cells. We also discuss distinct molecular mechanisms used by EZH2 to suppress BRCA1 functions.
    International journal of biological sciences 01/2012; 8(1):59-65. DOI:10.7150/ijbs.8.59 · 4.37 Impact Factor
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