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CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.
- Source :
-
Nature communications [Nat Commun] 2019 Nov 08; Vol. 10 (1), pp. 5114. Date of Electronic Publication: 2019 Nov 08. - Publication Year :
- 2019
-
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 <superscript>T416D</superscript> in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2 <superscript>T416D</superscript> 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.
- Subjects :
- Animals
Benzamides pharmacology
Biphenyl Compounds
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Cyclic N-Oxides
Cyclin-Dependent Kinase 2 antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein metabolism
Estrogen Receptor alpha genetics
Estrogen Receptor alpha metabolism
Female
Humans
Indolizines
Mammary Glands, Human drug effects
Mammary Glands, Human metabolism
Mammary Neoplasms, Experimental metabolism
Mice
Mice, Transgenic
Morpholines
Phosphorylation
Pyridinium Compounds pharmacology
Pyridones pharmacology
Receptor, ErbB-2 genetics
Receptor, ErbB-2 metabolism
Receptors, Progesterone metabolism
Triple Negative Breast Neoplasms metabolism
Cyclin-Dependent Kinase 2 metabolism
Enhancer of Zeste Homolog 2 Protein genetics
Estrogen Receptor alpha drug effects
Mammary Neoplasms, Experimental genetics
Triple Negative Breast Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31704972
- Full Text :
- https://doi.org/10.1038/s41467-019-13105-5