Journal Article

CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer

Ke, Baozhen, Deng, Rong, Hung, Mien-Chie, Chan, Li-Chuan, Pan, Dean N., Nie, Lei, Davidson, Nancy E., Hortobagyi, Gabriel N., Hsu, Jung-Mao, Xia, Weiya, Tang, Jun, Lin, Wan-Chi, Yamaguchi, Hirohito, Yao, Jun, Chu, Yu-Yi, Ko, How-Wen, Huo, Longfei, Zhu, Cihui, Hou, Junwei, Hsu, Yi-Hsin, Kleer, Celina G., Wei, Yongkun, Hsu, Jennifer L., Zhao, Xixi, Zhang, Fei, Han, Ye, Yang, Yi

2019

Overview

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2 T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2 T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC. EZH2 phosphorylation by CDK2 promotes progression of triple-negative breast cancer (TNBC). Here, the authors show that this signaling axis downregulates ERα, and thus combinatorial blockade of CDK2 and EZH2 sensitizes TNBC cells to tamoxifen.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/51 / 38/91 / 631/67/1059 / 631/67/1059/602 / 631/67/1347 / Animals / Benzamides - pharmacology / Breast cancer / Bridged Bicyclo Compounds, Heterocyclic - pharmacology / Cyclin E / Cyclin-dependent kinase 2 / Cyclin-Dependent Kinase 2 - antagonists & inhibitors / Cyclin-Dependent Kinase 2 - metabolism / Cyclin-dependent kinases / Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - metabolism / Epidermal growth factor / ErbB-2 protein / Estrogen Receptor alpha - drug effects / Estrogen Receptor alpha - genetics / Estrogen Receptor alpha - metabolism / Estrogens / Female / Growth factors / Homology / Humanities and Social Sciences / Humans / Kinases / Mammary gland / Mammary glands / Mammary Glands, Human - drug effects / Mammary Glands, Human - metabolism / Mammary Neoplasms, Experimental - genetics / Mammary Neoplasms, Experimental - metabolism / Mice / Mice, Transgenic / Mimicry / multidisciplinary / Phenotypes / Phosphorylation / Progesterone / Pyridinium Compounds - pharmacology / Pyridones - pharmacology / Receptor, ErbB-2 - genetics / Receptor, ErbB-2 - metabolism / Receptors, Progesterone - metabolism / Science / Science (multidisciplinary) / Tamoxifen / Transgenic mice / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Tumors