| First Author | Nie L | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 5114 |
| PubMed ID | 31704972 | Mgi Jnum | J:336875 |
| Mgi Id | MGI:6378054 | Doi | 10.1038/s41467-019-13105-5 |
| Citation | Nie L, et al. (2019) CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer. Nat Commun 10(1):5114 |
| abstractText | Triple-negative breast cancer (TNBC), which lacks estrogen receptor alpha (ERalpha), 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 ERalpha and converts TNBC to luminal ERalpha-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. |
