CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31704972.
- Also identified by DOI 10.1038/s41467-019-13105-5 and PMC identifier 6841924.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>T416D</sup> in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2<sup>T416D</sup> 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.
Medical subject headings
- Cyclin-Dependent Kinase 2
- Enhancer of Zeste Homolog 2 Protein
- Estrogen Receptor alpha
- Mammary Neoplasms, Experimental
- Triple Negative Breast Neoplasms