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根据受体表达特征，可以将雌激素受体、孕激素受体、人类表皮生长因子受体2（HER2）表达均为阴性的乳腺癌归类为三阴性乳腺癌；根据基因表达特征，70%～80%的三阴性乳腺癌属于具有基底细胞基因表达特征的基底样乳腺癌。既往研究已经发现，细胞分裂周期蛋白依赖型激酶2（CDK2）、组蛋白赖氨酸甲基转移酶（EZH2）几乎同时高表达于三阴性乳腺癌，而CDK2能够将EZH2特定部位T416磷酸化，可以诱发并且促进三阴性乳腺癌。 2019年11月8日，英国《自然》旗下《自然通讯》在线发表美国德克萨斯大学MD安德森癌症中心、德克萨斯大学休斯敦健康科学中心、德克萨斯大学奥斯汀主校、密歇根大学医学院、华盛顿大学弗雷德哈钦森癌症研究中心、上海交通大学医学院附属新华医院、中山大学附属肿瘤医院、西安交通大学第二附属医院、中国医科大学附属盛、台湾中国医药大学、台湾亚洲大学、卡塔尔哈迈德本哈利法大学的研究报告，发现CDK2或EZH2抑制剂可以将三阴性乳腺癌转化为雌激素受体阳性乳腺癌。 该研究表明，将EZH2特定部位T416磷酸化突变基因（EZH2[T416D]）转基因表达于乳腺，可以引起肿瘤出现三阴性乳腺癌表现型。将EZH2[T416D]同时表达于HER2转基因小鼠乳腺上皮，可以将HER2诱发的激素受体阳性乳腺癌重编程为基底样乳腺癌。CDK2或EZH2抑制剂可使雌激素受体重新表达，并将三阴性乳腺癌转化为雌激素受体阳性乳腺癌，从而使他莫昔芬能够靶向三阴性乳腺癌细胞。此外，CDK2或EZH2抑制剂联合他莫昔芬可以有效抑制肿瘤生长，并且显著改善三阴性乳腺癌肿瘤小鼠的生存。 因此，该研究结果表明，根据上述机制进行联合治疗，可能成为治疗三阴性乳腺癌的新方法。 Nat Commun. 2019 Nov 8. [Epub ahead of print] CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer. Lei Nie, Yongkun Wei, Fei Zhang, Yi-Hsin Hsu, Li-Chuan Chan, Weiya Xia, Baozhen Ke, Cihui Zhu, Rong Deng, Jun Tang, Jun Yao, Yu-Yi Chu, Xixi Zhao, Ye Han, Junwei Hou, Longfei Huo, How-Wen Ko, Wan-Chi Lin, Hirohito Yamaguchi, Jung-Mao Hsu, Yi Yang, Dean N. Pan, Jennifer L. Hsu, Celina G. Kleer, Nancy E. Davidson, Gabriel N. Hortobagyi, Mien-Chie Hung. The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; The University of Texas Health Science Center at Houston, Houston, TX, USA; Cancer Center, Sun Yat-Sen University, Guangzhou, China; The Second Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China; Shengjing Hospital of China Medical University, Shenyyang, China; Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar; The University of Texas at Austin, Austin, TX, USA; China Medical University, Taichung, Taiwan; Asia University, Taichung, Taiwan; University of Michigan Medical School, Ann Arbor, MI, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 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[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 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. DOI: 10.1038/s41467-019-13105-5
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