CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.
Lei NieYongkun WeiFei ZhangYi-Hsin HsuLi-Chuan ChanWeiya XiaBaozhen KeCihui ZhuRong DengJun TangJun YaoYu-Yi ChuXixi ZhaoYe HanJunwei HouLongfei HuoHow-Wen KoWan-Chi LinHirohito YamaguchiJung-Mao HsuYi YangDean N PanJennifer L HsuCelina G KleerNancy E DavidsonGabriel N HortobagyiMien-Chie HungPublished in: Nature communications (2019)
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.
Keyphrases
- estrogen receptor
- long non coding rna
- cell cycle
- long noncoding rna
- poor prognosis
- epidermal growth factor receptor
- combination therapy
- binding protein
- tyrosine kinase
- cell cycle arrest
- endothelial cells
- cell proliferation
- type diabetes
- transcription factor
- adipose tissue
- induced apoptosis
- signaling pathway
- advanced non small cell lung cancer
- protein kinase
- metabolic syndrome