Downregulation of Erbin in Her2-overexpressing breast cancer cells promotes cell migration and induces trastuzumab resistance.
Downregulation of Erbin in Her2-overexpressing breast cancer cells promotes cell migration and induces trastuzumab resistance.
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DOI：
10.1016/j.molimm.2013.04.007
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发表时间：
2013-11
影响因子：
3.6
通讯作者：
Dan Liu;M. Shi;C. Duan;Hongyu Chen;Yabin Hu;Zhengyan Yang;H. Duan;N. Guo
中科院分区：
文献类型：
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作者：
Dan Liu;M. Shi;C. Duan;Hongyu Chen;Yabin Hu;Zhengyan Yang;H. Duan;N. Guo
Erbin在正常上皮组织中广泛表达，并在上皮细胞的基底外侧膜上与Her2组成性结合。Erbin在ERK信号转导中的抑制作用已得到证实。然而，Erbin的表达是否在Her2过表达的乳腺癌中改变尚不清楚。关于Erbin在癌症进展中的作用的信息很少。在本研究中，我们证明了Erbin的水平在乳腺癌组织中显著下调或丢失。Erbin缺陷导致heregulin诱导的AKT活化的显著增强，并且Erbin的过表达不仅显著降低heregulin诱导的AKT磷酸化的强度，而且缩短其在Her2过表达乳腺癌细胞中的持续时间。Erbin的敲除显着促进细胞迁移，诱导乳腺癌细胞的侵袭表型，并拮抗治疗性抗体曲妥珠单抗的抗增殖作用。用AKT抑制剂GDC 0941处理显著逆转Erbin敲低对细胞迁移和曲妥珠单抗抗性的影响，这主要是由AKT的异常激活介导的。数据显示，Erbin是AKT激活的负调节因子，并表明Erbin可能在乳腺癌进展中发挥作用。
Erbin is ubiquitously expressed in normal epithelial tissues and constitutively associates with Her2 at the basolateral membranes in epithelial cells. The inhibitory role of Erbin in ERK signaling has been demonstrated. However, whether the expression of Erbin is altered in Her2-overexpressing breast cancer is unclear. There is little information regarding the function of Erbin in cancer progression. In the present study, we demonstrate that the level of Erbin is significantly downregulated or lost in breast cancer tissues. Erbin deficiency resulted in a dramatic enhancement in heregulin-induced AKT activation and overexpression of Erbin not only significantly decreased the intensity of heregulin-induced AKT phosphorylation but also shortened its duration in Her2-overexpressing breast cancer cells. Knockdown of Erbin remarkably promotes cell migration, induces invasive phenotype of breast cancer cells and antagonized the anti-proliferative effect of therapeutic antibody trastuzumab. Treatment with AKT inhibitor GDC0941 dramatically reversed the effects of Erbin knockdown on the cell migration and trastuzumab resistance, which is mainly mediated by aberrant activation of AKT. The data reveal that Erbin is a negative regulator of AKT activation and suggest that Erbin may play a role in breast cancer progression.