Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1.
Downregulation of EZH2 decreases growth of estrogen receptor-negative invasive breast carcinoma and requires BRCA1.
复制标题
EZH2的下调降低了雌激素受体阴性侵入性乳腺癌的生长，需要BRCA1。
DOI：
10.1038/onc.2008.433
复制
发表时间：
2009-02-12
期刊：
影响因子：
8
通讯作者：
Kleer, C. G.
中科院分区：
文献类型：
--
作者：
Gonzalez, M. E.;Li, X.;Toy, K.;DuPrie, M.;Ventura, A. C.;Banerjee, M.;Ljungman, M.;Merajver, S. D.;Kleer, C. G.
EZH2是细胞记忆的关键调节因子，其水平升高与乳腺癌雌激素受体（ER）负表达和疾病进展有关。在乳腺癌患者中，高水平的EZH2表明存在转移和预后不良。为了验证EZH2的缺失有助于ER阴性乳腺癌进展的假设，我们使用慢病毒系统抑制了ER阴性乳腺癌细胞MDA-MB-231和CAL51中EZH2的表达。EZH2敲低可抑制细胞增殖，延缓G2/M细胞周期转变，但不影响细胞凋亡。在体内，EZH2下调可显著降低乳腺异种移植物的生长，提高生存率。EZH2敲低上调BRCA1蛋白。值得注意的是，BRCA1敲低足以挽救EZH2下调对增殖、G2/M阻滞以及有丝分裂中Cdc25C和Cyclin B1蛋白高磷酸化水平的影响，这对进入有丝分裂至关重要。侵袭性ER阴性乳腺癌中EZH2过表达，BRCA1蛋白下调。综上所述，我们表明EZH2在体内和体外的ER阴性乳腺癌进展中发挥作用，并且BRCA1是EZH2增殖作用所必需的。阻断EZH2可能是预防和/或阻止ER阴性乳腺癌进展的主要靶点。
Increased levels of EZH2, a critical regulator of cellular memory, are associated with negative estrogen receptor (ER) expression and disease progression in breast cancer. High levels of EZH2 signal the presence of metastasis and poor outcome in breast cancer patients. To test the hypothesis that deregulation of EZH2 contributes to ER negative breast cancer progression, EZH2 expression was inhibited in ER negative breast cancer cells MDA-MB-231 and CAL51 using a lentivirus system. EZH2 knockdown decreased proliferation and delayed the G2/M cell cycle transition, while not affecting apoptosis. In vivo, EZH2 down-regulation significantly decreased breast xenograft growth and improved survival. EZH2 knockdown up regulated BRCA1 protein. Of note, BRCA1 knockdown was sufficient to rescue the effects of EZH2 down-regulation in proliferation, G2/M arrest, and on the levels of hyperphosphorlated mitotic Cdc25C and Cyclin B1 proteins, crucial for entry into mitosis. Invasive ER negative breast carcinomas show significant overexpression of EZH2 and down-regulation of BRCA1 proteins. Taken together, we show that EZH2 plays a role in ER negative breast cancer progression in vivo and in vitro, and that BRCA1 is required for the proliferative effects of EZH2. Blockade of EZH2 may provide a prime target to prevent and/or halt ER negative breast cancer progression.
登录
查看更多内容
影响因子：
4.3
作者：
Bae, I;Rih, JK;Rosen, EM
通讯作者：
Rosen, EM
影响因子：
56.9
作者：
Cortez, D;Wang, Y;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
21.3
作者：
Bulavin, DV;Higashimoto, Y;Fornace, AJ
通讯作者：
Fornace, AJ
影响因子：
56.9
作者：
Cao, R;Wang, LJ;Zhang, Y
通讯作者：
Zhang, Y
影响因子：
10.5
作者：
Kuzmichev, A;Nishioka, K;Reinberg, D
通讯作者：
Reinberg, D