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; Mien Chie Hung

doi:10.1038/s41467-019-13105-5

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 HsuYi Yang, Dean N. Pan, Jennifer L. Hsu, Celina G. Kleer, Nancy E. Davidson, Gabriel N. Hortobagyi, Mien Chie Hung

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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 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.

Original language	English (US)
Article number	5114
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13105-5
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Nie, L., Wei, Y., Zhang, F., Hsu, Y.-H., Chan, L. C., Xia, W., Ke, B., Zhu, C., Deng, R., Tang, J., Yao, J., Chu, Y. Y., Zhao, X., Han, Y., Hou, J., Huo, L., Ko, H. W., Lin, W. C., Yamaguchi, H., ... Hung, M. C. (2019). CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer. Nature communications, 10(1), Article 5114. https://doi.org/10.1038/s41467-019-13105-5

Nie, L , Wei, Y, Zhang, F, Hsu, Y-H, Chan, LC, Xia, W, Ke, B, Zhu, C, Deng, R, Tang, J, Yao, J, Chu, YY, Zhao, X, Han, Y, Hou, J, Huo, L, Ko, HW, Lin, WC, Yamaguchi, H, Hsu, J-M, Yang, Y, Pan, DN, Hsu, JL, Kleer, CG, Davidson, NE, Hortobagyi, GN & Hung, MC 2019, 'CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer', Nature communications, vol. 10, no. 1, 5114. https://doi.org/10.1038/s41467-019-13105-5

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title = "CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer",

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.",

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

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doi = "10.1038/s41467-019-13105-5",

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AU - Nie, Lei

AU - Wei, Yongkun

AU - Zhang, Fei

AU - Hsu, Yi-Hsin

AU - Chan, Li Chuan

AU - Xia, Weiya

AU - Ke, Baozhen

AU - Zhu, Cihui

AU - Deng, Rong

AU - Tang, Jun

AU - Yao, Jun

AU - Chu, Yu Yi

AU - Zhao, Xixi

AU - Han, Ye

AU - Hou, Junwei

AU - Huo, Longfei

AU - Ko, How Wen

AU - Lin, Wan Chi

AU - Yamaguchi, Hirohito

AU - Hsu, Jung-Mao

AU - Yang, Yi

AU - Pan, Dean N.

AU - Hsu, Jennifer L.

AU - Kleer, Celina G.

AU - Davidson, Nancy E.

AU - Hortobagyi, Gabriel N.

AU - Hung, Mien Chie

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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

Abstract

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MD Anderson CCSG core facilities

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