Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells.
Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells.
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DOI：
10.1158/0008-5472.can-12-2149
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发表时间：
2013-02-15
期刊：
影响因子：
11.2
通讯作者：
Raz A
中科院分区：
文献类型：
--
作者：
Kho DH;Nangia-Makker P;Balan V;Hogan V;Tait L;Wang Y;Raz A
曲妥珠单抗（赫赛汀®）是一种有效的靶向治疗HER 2过表达的人乳腺癌。然而，许多HER 2阳性患者最初或最终对这种治疗产生耐药性，因此阐明乳腺癌细胞中出现的曲妥珠单抗耐药机制具有临床重要性。在这里，我们表明，自分泌运动因子（AMF）结合到HER 2和诱导切割的胞外结构域删除和组成型活性形式p95 HER 2。机制研究表明，AMF与HER 2的相互作用触发HER 2磷酸化和金属蛋白酶介导的胞外域脱落，激活PI 3 K和MAPK信号传导，并消除曲妥珠单抗抑制乳腺癌细胞生长的能力。此外，我们发现HER 2表达和AMF分泌在乳腺癌细胞中呈负相关。基于AMF可能导致HER 2介导的乳腺癌进展的证据，我们的研究结果表明AMF-HER 2相互作用可能是对曲妥珠单抗耐药的乳腺癌患者治疗管理的新靶点。
Trastuzumab (Herceptin®) is an effective targeted therapy in HER2 overexpressing human breast carcinoma. However, many HER2-positive patients initially or eventually become resistant to this treatment, so elucidating mechanisms of trastuzumab resistance that emerge in breast carcinoma cells is clinically important. Here we show that autocrine motility factor (AMF) binds to HER2 and induces cleavage to the ectodomain-deleted and constitutively active form p95HER2. Mechanistic investigations indicated that interaction of AMF with HER2 triggers HER2 phosphorylation and metalloprotease-mediated ectodomain shedding, activating PI3K and MAPK signaling and ablating the ability of trastuzumab to inhibit breast carcinoma cell growth. Further, we found that HER2 expression and AMF secretion were inversely related in breast carcinoma cells. Based on this evidence that AMF may contribute to HER2-mediated breast cancer progression, our findings suggest that AMF-HER2 interaction might be a novel target for therapeutic management of breast cancer patients whose disease is resistant to trastuzumab.