Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer

Yomtoubian, Shira; Lee, Sharrell B.; Verma, Akanksha; Izzo, Franco; Markowitz, Geoffrey J.; Choi, Hyejin; Cerchietti, Leandro; Vahdat, Linda T.; Brown, Kristy A.; Andreopoulou, Eleni; Elemento, Olivier; Chang, Jenny C.; Inghirami, Giorgio; Gao, Dingcheng; Ryu, Seongho; Mittal, Vivek

doi:10.1016/j.celrep.2019.12.056

Cited by 71 publications

(72 citation statements)

References 73 publications

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“…EZH2 inhibition differentiates EZH2 high basal cells to a luminal-like phenotype by derepressing GATA3 and renders them sensitive to endocrine therapy. 20 Polycomb inhibitors, especially those directed against the PRC2 catalytic subunit EZH2 have shown responses in preclinical studies of cancer therapy. 9…”

Section: Discussionmentioning

confidence: 99%

Association of axillary node status with clinicopathological characteristics and expression of EZH2 and CD44 in primary breast ductal carcinoma

et al. 2020

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Objective: In order to enhance the prognostic benefit of new molecular markers, the aim of this study was to identify possible association of axillary lymph node (ALN) status and pN with clinicopathological characteristics and expression of EZH2 and CD44 in invasive ductal carcinoma (IDC) of the breast. Methods: The investigation included 106 patients with IDC who had undergone radical mastectomy at the Clinic of Endocrine Surgery in Nis. Clinicopathologic parameters and immunohistochemical expression of EZH2 and CD44 in primary IDC were investigated in relation to ALN status and pN. Results: Our univariate analysis established that Т3-Т4 stage, high EZH2, and high EZH2 with ER- were associated with ALN metastasis (p=0.014; 0.003; 0.013). Decreased probability for ALN involvement was found with Т1 stage, and low EZH2 with ER+ (p=0.032; 0.022). Multivariant analysis established that high EZH2 in cancer cells was associated with high risk for ALN metastases (p=0.004); T1 tumors were associated with low risk (p=0.037). Higher pN was associated with high EZH2, high EZH2 with ER-, as well as an advanced clinical and disease stage (p=0.006; 0.001; p=0.002, 0.001). Lower pN was associated with ER+, and ER+ with low EZH2 (p= 0.004; 0.012). CD44 was not associated with ALN involvement, nor with pN. Conclusions: This study revealed association of EZH2 with ALN metastases, where disease stage and expression profiles of EZH2 and ER may have affected regional pN. doi: https://doi.org/10.12669/pjms.36.7.2954 How to cite this:Djordjevic M, Karanikolic A, Velickovic L, Milentijevic M. Association of axillary node status with clinicopathological characteristics and expression of EZH2 and CD44 in primary breast ductal carcinoma. Pak J Med Sci. 2020;36(7):---------. doi: https://doi.org/10.12669/pjms.36.7.2954 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Association of axillary node status with clinicopathological characteristics and expression of EZH2 and CD44 in primary breast ductal carcinoma

et al. 2020

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“…EZH2 is a catalytic component of the polycomb repressive complex 2 (PRC2), which uses its HMT activity to catalyze the trimethylation of lysine at position 27 of histone H3, resulting in the suppression of downstream tumor suppressor genes such as E-cadherin, P16 INK4α , P57 , and PSP94 [ 30 ]. At present, numerous experimental results indicate that EZH2 overexpression promotes proliferation, migration and invasion of cancer cells in endometrial cancer, lung cancer, melanoma, breast cancer, bladder cancer and colorectal cancer [ 31 – 33 ]. EZH2 enhances cell cycle progression and activating VEGF / AKT signaling in non-small cell lung cancer (NSCLC) cells [ 34 , 35 ].…”

Section: The Biological Characteristics Of Hmtsmentioning

confidence: 99%

Histone methyltransferase and drug resistance in cancers

Yang

Zhang

et al. 2020

J Exp Clin Cancer Res

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A number of novel anticancer drugs have been developed in recent years. However, the mortality of cancer patients remains high because of the emergence of drug resistance. It was reported that drug resistance might involved in changes in gene expression without changing genotypes, which is similar to epigenetic modification. Some studies indicated that targeting histone methyltransferase can reverse drug resistance. Hence, the use of histone methyltransferase inhibitors or histone demethylase inhibitors opens new therapeutic approaches for cancer treatment. While the relationship between histone methyltransferase and tumor resistance has been determined, there is a lack of updated review on the association between them. In this review, we summarized the mechanisms of histone methyltransferases in cancer drug resistance and the therapeutic strategies of targeting histone methyltransferase to reverse drug resistance.

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“…Wang et al describe that low KDM6A expression predicts poor survival in breast cancer [ 203 ], while Kim JH et al report that high expression is associated with poor prognosis [ 204 ]. However, later studies support an oncogenic role for KDM6A as it is overexpressed in breast cancer and correlates with cancer grades [ 189 , 205 ]. Furthermore, knockdown of KDM6A decreases cancer cell proliferation, invasion, and lung colonization [ 162 , 189 ].…”

Section: Alterations In the Erasers Of Methylation Of H3k27 In Canmentioning

confidence: 99%

Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity

Das

2020

Cancers

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Properly timed addition and removal of histone 3 lysine 27 tri-methylation (H3K27me3) is critical for enabling proper differentiation throughout all stages of development and, likewise, can guide carcinoma cells into altered differentiation states which correspond to poor prognoses and treatment evasion. In early embryonic stages, H3K27me3 is invoked to silence genes and restrict cell fate. Not surprisingly, mutation or altered functionality in the enzymes that regulate this pathway results in aberrant methylation or demethylation that can lead to malignancy. Likewise, changes in expression or activity of these enzymes impact cellular plasticity, metastasis, and treatment evasion. This review focuses on current knowledge regarding methylation and de-methylation of H3K27 in cancer initiation and cancer cell plasticity.

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Inhibition of EZH2 Catalytic Activity Selectively Targets a Metastatic Subpopulation in Triple-Negative Breast Cancer

Cited by 71 publications

References 73 publications

Association of axillary node status with clinicopathological characteristics and expression of EZH2 and CD44 in primary breast ductal carcinoma

Association of axillary node status with clinicopathological characteristics and expression of EZH2 and CD44 in primary breast ductal carcinoma

Histone methyltransferase and drug resistance in cancers

Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity

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