NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling.
NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling.
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NUMB 通过拮抗 Notch 信号传导负向调节三阴性乳腺癌的上皮间质转化
DOI：
10.18632/oncotarget.11062
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发表时间：
2016-09-20
期刊：
影响因子：
--
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Zhang J;Shao X;Sun H;Liu K;Ding Z;Chen J;Fang L;Su W;Hong Y;Li H;Li H
三阴性乳腺癌（TNBC）是乳腺癌的积极亚型，具有较高的早期复发和转移率，经常与上皮 - 间质转变（EMT）的异常激活有关。尽管如此，在TNBC进展过程中如何启动和调节EMT尚未得到充分了解。在这里，我们报告说Numb是人类乳腺上皮细胞和乳腺癌细胞中EMT的负调节剂。麻木表达降低与TNBC中EMT的升高显着相关。相反，麻木的过表达强烈减弱了TNBC细胞系的EMT程序和转移。有趣的是，我们表明Numb采用不同的分子机制来调节EMT。在正常的乳腺上皮细胞和表达野生型p53的乳腺癌细胞中，麻木通过稳定p53抑制EMT。但是，在TNBC细胞中，麻木的损失通过激活Notch信号传导促进了EMT程序。与这些发现一致，低麻木表达和高缺口活性与患者的TNBC亚型显着相关。总的来说，这些发现揭示了在调节乳腺肿瘤EMT的调节中，尤其是在TNBC中，麻木的新分子机制。
Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC.