Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 20009, China.
Nat Commun. 2019 Nov 8;10(1):5114. doi: 10.1038/s41467-019-13105-5.
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 in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2 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.
三阴性乳腺癌（TNBC）缺乏雌激素受体 α（ERα）、孕激素受体和人表皮生长因子受体 2（HER2）的表达，与基底样乳腺癌密切相关。此前，我们和其他人报告称，细胞周期蛋白 E/细胞周期依赖性激酶 2（CDK2）在 T416 位（pT416-EZH2）使增强子结合抑制因子 2（EZH2）磷酸化。在这里，我们展示了在乳腺中过表达磷酸化模拟 EZH2 突变体 EZH2 会导致具有 TNBC 表型的肿瘤。在 HER2/neu 转基因小鼠的乳腺上皮中共同表达 EZH2 会将 HER2 驱动的腔肿瘤重新编程为基底样肿瘤。CDK2 或 EZH2 抑制剂的药理学抑制允许 ERα 的重新表达，并将 TNBC 转化为腔 ERα 阳性，使 TNBC 细胞可被他莫昔芬靶向。此外，CDK2 或 EZH2 抑制剂与他莫昔芬的联合有效地抑制了肿瘤的生长，并显著提高了携带 TNBC 肿瘤的小鼠的存活率，这表明基于机制的联合治疗可能是治疗 TNBC 的一种替代方法。
