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

Lei Nie, Yongkun Wei, Fei Zhang, Yi-Hsin Hsu, Li-Chuan Chan, Weiya Xia, Baozhen Ke, Cihui Zhu, Rong Deng, Jun Tang, Jun Yao, Yu-Yi Chu, Xixi Zhao, Ye Han, Junwei Hou, Longfei Huo, How-Wen Ko, Wan-Chi Lin, Hirohito Yamaguchi, Jung-Mao Hsu, Yi Yang, Dean N. Pan, Jennifer L. Hsu, Celina G. Kleer, Nancy E. Davidson, Gabriel N. Hortobagyi and Mien-Chie Hung ()
Additional contact information
Lei Nie: The University of Texas MD Anderson Cancer Center
Yongkun Wei: The University of Texas MD Anderson Cancer Center
Fei Zhang: The University of Texas MD Anderson Cancer Center
Yi-Hsin Hsu: The University of Texas MD Anderson Cancer Center
Li-Chuan Chan: The University of Texas MD Anderson Cancer Center
Weiya Xia: The University of Texas MD Anderson Cancer Center
Baozhen Ke: The University of Texas MD Anderson Cancer Center
Cihui Zhu: The University of Texas MD Anderson Cancer Center
Rong Deng: The University of Texas MD Anderson Cancer Center
Jun Tang: The University of Texas MD Anderson Cancer Center
Jun Yao: The University of Texas MD Anderson Cancer Center
Yu-Yi Chu: The University of Texas MD Anderson Cancer Center
Xixi Zhao: The University of Texas MD Anderson Cancer Center
Ye Han: The University of Texas MD Anderson Cancer Center
Junwei Hou: The University of Texas MD Anderson Cancer Center
Longfei Huo: The University of Texas MD Anderson Cancer Center
How-Wen Ko: The University of Texas MD Anderson Cancer Center
Wan-Chi Lin: The University of Texas MD Anderson Cancer Center
Hirohito Yamaguchi: The University of Texas MD Anderson Cancer Center
Jung-Mao Hsu: The University of Texas MD Anderson Cancer Center
Yi Yang: The University of Texas MD Anderson Cancer Center
Dean N. Pan: The University of Texas MD Anderson Cancer Center
Jennifer L. Hsu: The University of Texas MD Anderson Cancer Center
Celina G. Kleer: University of Michigan Medical School
Nancy E. Davidson: Fred Hutchinson Cancer Research Center
Gabriel N. Hortobagyi: The University of Texas MD Anderson Cancer Center Houston
Mien-Chie Hung: The University of Texas MD Anderson Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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 EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D 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.

Date: 2019
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DOI: 10.1038/s41467-019-13105-5

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