Binding of anterior gradient 2 and estrogen receptor-α: Dual critical roles in enhancing fulvestrant resistance and IGF-1-induced tumorigenesis of breast cancer
Binding of anterior gradient 2 and estrogen receptor-α: Dual critical roles in enhancing fulvestrant resistance and IGF-1-induced tumorigenesis of breast cancer
复制标题
前梯度 2 和雌激素受体 α 的结合：在增强氟维司群耐药性和 IGF-1 诱导的乳腺癌肿瘤发生中的双重关键作用
DOI：
10.1016/j.canlet.2016.04.003
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发表时间：
2016-07-10
期刊：
影响因子：
9.7
通讯作者：
Li, Dawei
中科院分区：
文献类型：
--
作者：
Li, Zheqi;Zhu, Qi;Li, Dawei
前部梯度2(AGR2)是一种重要的癌症生物标志物，已被广泛报道与雌激素受体(ER)阳性乳腺癌的发生有关。在这里，我们揭示了胞质和外源AGR2通过与ER-α的相互作用，分别在增强弗维斯特抵抗和IGF-1诱导的癌症发生中的作用。我们目前的研究表明，MCF-7和T47D细胞中内源性AGR2水平与氟维斯特耐药呈正相关。在MCF-7细胞中，AGR2基因的敲除强烈地增强了富维斯特诱导的G1期停滞，并加速了富维斯特诱导的ER-α的降解。此外，细胞内AGR2与ER-α具有功能性相互作用。另一方面，细胞外AGR2显著促进IGF-1诱导的细胞增殖、迁移、细胞周期进展和上皮-间充质转化。细胞外AGR2还可增强IGF-1下游信号。我们还发现ER-α作为一种潜在的介体与胞外AGR2和IGF-1受体发生特异性的相互作用。最后，我们揭示了AGR2单抗的辅助治疗增强了弗维斯特和林西替尼对乳腺癌发展的抑制作用。我们的发现首次指出了细胞内和细胞外AGR2的不同功能，为以AGR2为靶点的抗肿瘤治疗的发展提供了新的见解。(C)爱思唯尔爱尔兰有限公司出版的2016年。
Anterior gradient 2 (AGR2), an essential cancer biomarker, has been widely reported to be associated with estrogen receptor (ER) positive breast cancer development. Here, we uncovered the role of cytoplasmic and exogenous AGR2, through interaction with ER-alpha, in enhancing fulvestrant resistance and IGF-1-induced carcinogenesis respectively. Our present study revealed that the endogenous AGR2 level positively correlates with fulvestrant resistance in MCF-7 and T47D cells. AGR2-knockdown in MCF-7 cells strongly enhances the fulvestrant-induced G1 phase arrest and accelerates the fulvestrant-induced ER-alpha degradation. Furthermore, intracellular AGR2 exhibits a functional interaction with ER-alpha. On the other hand, extracellular AGR2 remarkably promotes the IGF-1-induced cell proliferation, migration, cell cycle progression and epithelial-mesenchymal transition. Extracellular AGR2 also enhances IGF-1 downstream signaling. We also showed that ER-alpha specifically interacts with both extracellular AGR2 and IGF-1 receptor as a potential intermediator. Finally, we revealed that the adjuvant therapy of AGR2 monoclonal antibody enhances the inhibitory effects of fulvestrant and linsitinib toward breast cancer development. Our findings, for the first time, point out the different functions of intra- and extra-cellular AGR2, providing new insights into the development of anti-tumor therapies targeting AGR2. (C) 2016 Published by Elsevier Ireland Ltd.