Zhang Jianchao, Shao Ximing, Sun Haiyan, Liu Ke, Ding Zhihao, Chen Juntao, Fang Lijing, Su Wu, Hong Yang, Li Huashun, Li Hongchang
Shenzhen Key Laboratory for Molecular Biology of Neural Development, Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Oncotarget. 2016 Sep 20;7(38):61036-61053. doi: 10.18632/oncotarget.11062.
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.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，早期复发和转移率较高，常与上皮-间质转化（EMT）的异常激活相关。然而，在TNBC进展过程中EMT是如何启动和调控的，目前尚不清楚。在此，我们报道NUMB在人乳腺上皮细胞和乳腺癌细胞中均为EMT的负调控因子。NUMB表达降低与TNBC中EMT升高显著相关。相反，NUMB的过表达强烈减弱了TNBC细胞系的EMT程序和转移能力。有趣的是，我们发现NUMB采用不同的分子机制来调控EMT。在表达野生型p53的正常乳腺上皮细胞和乳腺癌细胞中，NUMB通过稳定p53来抑制EMT。然而，在TNBC细胞中，NUMB的缺失通过激活Notch信号促进了EMT程序。与这些发现一致，患者中低NUMB表达和高Notch活性与TNBC亚型显著相关。总体而言，这些发现揭示了NUMB在调控乳腺肿瘤EMT，尤其是TNBC中的新分子机制。
