Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers.
Endophilin A2 promotes HER2 internalization and sensitivity to trastuzumab-based therapy in HER2-positive breast cancers.
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DOI：
10.1186/s13058-017-0900-z
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发表时间：
2017-10-03
期刊：
影响因子：
--
通讯作者：
Craig AW
中科院分区：
文献类型：
--
作者：
Baldassarre T;Truesdell P;Craig AW
人表皮生长因子受体-2（HER 2）是扩增的，并且是具有高转移率的人乳腺癌亚组中的临床靶点。涉及抗体曲妥珠单抗和曲妥珠单抗-美坦新偶联物（T-DM 1）的靶向治疗大大改善了HER 2阳性（HER 2+）乳腺癌患者的结局。然而，对这些靶向治疗的耐药性可能会发展并限制其疗效。在这里，我们测试了HER 2+乳腺癌模型中内吞衔接蛋白endophilin A2（Endo II）的参与，以及它们对曲妥珠单抗和T-DM 1治疗的反应。采用免疫组化方法分析乳腺肿瘤及淋巴结转移灶中Endo II的表达。在HER 2+癌细胞系（SK-BR-3和HCC 1954）中实现Endo II的稳定沉默，以测试Endo II对HER 2水平、定位和信号传导、细胞运动性和肿瘤转移的影响。使用实时细胞运动性和细胞毒性测定测试Endo II沉默对HER 2+癌细胞对曲妥珠单抗或T-DM 1治疗的应答的影响。在HER 2阳性肿瘤中检测到高Endo II蛋白表达，并且在mRNA水平上与淋巴结阳性HER 2+乳腺癌的总体生存率较差相关。在HER 2+细胞系中，Endo II的稳定沉默导致细胞表面HER 2水平升高，表皮生长因子诱导的HER 2内化受损，并减少下游效应激酶Akt和Erk的信号传导。Endo II沉默还导致体外HER 2+癌细胞的迁移和侵袭减少，并在小鼠尾静脉注射后损害肺种植。此外，Endo II沉默还损害了响应曲妥珠单抗的HER 2内化，并导致用T-DM 1处理的HER 2+癌细胞中的细胞毒性反应降低。我们的研究提供了与曲妥珠单抗或T-DM 1有效治疗相关的HER 2+癌细胞运动和HER 2运输中Endo II功能的新证据。因此，Endo II的差异表达可能与对基于曲妥珠单抗的HER 2+癌症治疗的敏感性或耐药性有关。本文的在线版本（doi：10.1186/s13058-017-0900-z）包含补充材料，可供授权用户使用。
Human epidermal growth factor receptor-2 (HER2) is amplified and a clinical target in a subset of human breast cancers with high rates of metastasis. Targeted therapies involving the antibody trastuzumab and trastuzumab-emtansine (T-DM1) have greatly improved outcomes for HER2-positive (HER2+) breast cancer patients. However, resistance to these targeted therapies can develop and limit their efficacy. Here, we test the involvement of the endocytic adaptor protein endophilin A2 (Endo II) in HER2+ breast cancer models, and their responses to treatments with trastuzumab and T-DM1. Endo II expression in human breast tumors and lymph node metastases were analyzed by immunohistochemistry. Stable silencing of Endo II was achieved in HER2+ cancer cell lines (SK-BR-3 and HCC1954) to test Endo II effects on HER2 levels, localization and signaling, cell motility and tumor metastasis. The effects of Endo II silencing on the responses of HER2+ cancer cells to trastuzumab or T-DM1 treatments were tested using real-time cell motility and cytotoxicity assays. High Endo II protein expression was detected in HER2-positive tumors, and was linked to worse overall survival in node-positive HER2+ breast cancers at the mRNA level. Stable silencing of Endo II in HER2+ cell lines led to elevated levels of HER2 on the cell surface, impaired epidermal growth factor-induced HER2 internalization, and reduced signaling to downstream effector kinases Akt and Erk. Endo II silencing also led to decreased migration and invasion of HER2+ cancer cells in vitro, and impaired lung seeding following tail vein injection in mice. In addition, Endo II silencing also impaired HER2 internalization in response to Trastuzumab, and led to reduced cytotoxicity response in HER2+ cancer cells treated with T-DM1. Our study provides novel evidence of Endo II function in HER2+ cancer cell motility and trafficking of HER2 that relates to effective treatments with trastuzumab or T-DM1. Thus, differential expression of Endo II may relate to sensitivity or resistance to trastuzumab-based therapies for HER2+ cancers. The online version of this article (doi:10.1186/s13058-017-0900-z) contains supplementary material, which is available to authorized users.
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影响因子：
7.4
作者：
Boero S;Morabito A;Banelli B;Cardinali B;Dozin B;Lunardi G;Piccioli P;Lastraioli S;Carosio R;Salvi S;Levaggi A;Poggio F;D'Alonzo A;Romani M;Del Mastro L;Poggi A;Pistillo MP
通讯作者：
Pistillo MP
影响因子：
45.3
作者：
Cobleigh, MA;Vogel, CL;Slamon, DJ
通讯作者：
Slamon, DJ
影响因子：
4
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通讯作者：
Stow, Jennifer L.
影响因子：
4.8
作者：
Fan, Huaping;Zhao, Xiaofeng;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
影响因子：
64.8
作者：
HENKEMEYER, M;ROSSI, DJ;PAWSON, T
通讯作者：
PAWSON, T