Decreased expression of EZH2 is associated with upregulation of ER and favorable outcome to tamoxifen in advanced breast cancer. Breast Cancer Research Treatment, 125:387-394

Department of Medical Oncology, Erasmus MC/Daniel den Hoed Cancer Center/Josephine Nefkens Institute, Rotterdam, The Netherlands.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 03/2010; 125(2):387-94. DOI: 10.1007/s10549-010-0836-9
Source: PubMed


The purpose of this study is to investigate EZH2 in a large series of breast cancer patients for its prognostic and predictive value, and to evaluate its functional role in treatment response in vitro. EZH2 levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens and related to clinicopathologic factors and disease outcome. EZH2 expression was downregulated with siRNAs in MCF7, to assess expression alterations of putative EZH2 downstream genes and to determine cell numbers after treatment with the anti-estrogen ICI 164384. In 688 lymph node-negative patients who did not receive adjuvant systemic therapy, EZH2 was not significantly correlated with metastasis-free survival (MFS). In 278 patients with advanced disease treated with first-line tamoxifen monotherapy, the tertile with highest EZH2 levels was associated with the lowest clinical benefit (OR = 0.48; P = 0.02) and with a shorter progression-free survival (PFS) in both univariate (HR = 1.80; P < 0.001) and multivariate analysis, including traditional factors (HR = 1.61; P = 0.004). In vitro, EZH2 silencing in MCF7 caused a 38% decrease in cell numbers (P < 0.001) whereas ICI 164384 treatment resulted in a 25% decrease (P < 0.001) compared to controls. Combining EZH2 silencing with ICI treatment reduced cell numbers with 67% (P < 0.001) compared to control conditions. EZH2 downregulation was associated with an almost two-fold upregulation of the estrogen receptor alpha (ER) (P = 0.001). In conclusion, EZH2 has no prognostic value in breast cancer. High levels of EZH2 are associated with poor outcome to tamoxifen therapy in advanced breast cancer. Downregulated EZH2 leads to upregulation of the ER and better response to anti-estrogens.

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Available from: Els M J J Berns
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    • "EZH2 levels were elevated in patients with invasive breast carcinoma compared with normal or atypical hyperplasia.16 Furthermore, it has been shown that high levels of EZH2 are associated with poor outcome to tamoxifen therapy in advanced breast cancer.17,18 Recently, EZH2-mediated epigenetic repression of DNA damage repair in breast tumor initiating cells was identified as a mechanism that could promote expansion of breast tumor initiating cells, and may contribute to cancer progression.18 "
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    ABSTRACT: Accumulating evidence shows that enhancer of zeste homolog 2 (E2H2) is upregulated in a broad range of cancer types, such as breast cancer, prostate cancer, ovarian cancer, and colon cancer. Therefore, inhibiting EZH2 expression may be a promising strategy for anticancer therapy. This review focuses on the current understanding of the mechanisms underlying EZH2 regulation that are involved in cancer progression. Also, it introduces two EZH2 inhibitors that target EZH2 and could be potentially applied in the treatment of cancer in the future.
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    • "A second possible mechanism involves the enhancer of zeste homolog 2 (EZH2), which is activated by TNFa in an NFκB -dependent manner [62]. EZH2 is a member of the polycomb repressor complex 2 and regulates gene expression via trimethyla-tion of lysine 27 on histone 3. Silencing of EZH2 in breast cancer cell lines leads to a nearly twofold increased expression of ER [63], suggesting that EZH2 activation secondary to NFκB activation may be involved in silencing of ER expression. Finally, NFκB - and more specifically RelB - is able to repress ER expression by means of BLIMP1, a zinc finger protein that inhibits ER transcription [64]. "
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    • "Tumor protein expression levels of ER and progesterone receptor (PgR) were determined and used to classify tumors as ER- and/or PgR-positive as described previously [4, 14]. The following criteria were applied to include breast tumor specimens for final analysis in this study: (1) sufficient frozen tumor material, (2) more than 30% epithelial tumor cell nuclei in haematoxylin/eosin-stained sections, and (3) specimen of good RNA quality according to predefined criteria [15]. "
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    ABSTRACT: For patients with metastatic breast cancer, we previously described that increased EZH2 expression levels were associated with an adverse outcome to tamoxifen therapy. Main objective of the present study is to investigate miR-26a and miR-101 levels, which both target EZH2, for their association with molecular pathways and with efficacy of tamoxifen as first-line monotherapy for metastatic breast cancer. Expression levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens of 235 estrogen receptor-α (ER)-positive patients. Pathway analysis was performed on microarray data available for 65 of these tumors. Logistic regression and Cox uni- and multivariate analysis were performed to relate expression levels with clinical benefit and time to progression (TTP). Increasing levels of miR-26a were significantly (P < 0.005) associated with both clinical benefit and prolonged TTP, whereas miR-101 was not. Cell cycle regulation and CCNE1 and CDC2 were the only significant overlapping pathway and genes differentially expressed between tumors with high and low levels of miR-26a and EZH2, respectively. In addition, increasing mRNA levels of CCNE1 (P < 0.05) and CDC2 (P < 0.001) were related to poor outcome. Multivariate analysis revealed miR-26a and CDC2 as an optimal set of markers associated with outcome on tamoxifen therapy, independently of traditional predictive factors. To summarize, only miR-26a levels are related with treatment outcome. Cell cycle regulation is the only overlapping pathway linked to miR-26a and EZH2 levels. Low mRNA levels of EZH2, CCNE1, and CDC2, and high levels of miR-26a are associated with favorable outcome on tamoxifen. Electronic supplementary material The online version of this article (doi:10.1007/s10549-011-1877-4) contains supplementary material, which is available to authorized users.
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