ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer cells
ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer cells
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DOI：
10.1210/en.2008-0351
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Nicholson, Robert I.
中科院分区：
文献类型：
--
作者：
Taylor, Kathryn M.;Vichova, Petra;Nicholson, Robert I.
他莫昔芬等抗雌激素药物是雌激素受体阳性乳腺癌的主要治疗手段。然而，它们的有效性受到内分泌抵抗的发展的限制，使肿瘤重新生长和发展。重要的是，获得性三苯氧胺耐药(TamR细胞)的体外MCF7细胞模型表现出侵袭性、侵袭性表型，其中上皮生长因子受体/IGF-I受体/Src信号通路的激活起着关键作用。在这项研究中，我们报告了TAMR细胞锌和锌转运体ZIP7[溶质载体家族39(锌转运体)成员7，也称为SLC39A7和HKE4]的水平增加，导致对外源性锌的反应增强，表现为显著增加生长因子受体的激活，导致生长和侵袭增加。使用小干扰RNA去除ZIP7，通过降低细胞内锌水平来破坏上皮生长因子受体/IGF-I受体/Src信号的激活。同样，它也可以阻断HER2、-3和-4的激活。这些数据表明，细胞内锌水平可能是决定生长因子反应的关键因素，以锌转运蛋白为靶点可能具有新的治疗意义。我们表明，ZIP7是锌从细胞内储存到细胞质重新分配的关键成分，因此，对于锌诱导的磷酸酶抑制是必不可少的，而磷酸酶导致生长因子受体的激活。因此，去除ZIP7提供了一种有效抑制锌诱导的生长因子受体激活的方法，并提供了一种靶向多个生长因子途径、增加肿瘤杀伤力和防止乳腺癌进一步耐药的机制。
Antiestrogens such as tamoxifen are the mainstay of treatment for estrogen receptor-positive breast cancer. However, their effectiveness is limited by the development of endocrine resistance, allowing tumor regrowth and progression. Importantly, in vitro MCF7 cell models of acquired tamoxifen resistance (TamRcells) display an aggressive, invasive phenotype in which activation of epithelial growth factor receptor/IGF-I receptor/Src signaling plays a critical role. In this study, we report that TamR cells have increased levels of zinc and zinc transporter, ZIP7 [solute carrier family 39 (zinc transporter) member 7, also known as SLC39A7 and HKE4], resulting in an enhanced response to exogenous zinc, which is manifested as a greatly increased growth factor receptor activation, leading to increased growth and invasion. Removal of ZIP7, using small interfering RNA, destroys this activation of epithelial growth factor receptor/IGF-I receptor/Src signaling by reducing intracellular zinc levels. Similarly, it also blocks the activation of HER2, -3, and -4. These data suggest that intracellular zinc levels may be a critical factor in determining growth factor responses and that the targeting of zinc transporters may have novel therapeutic implications. We show that ZIP7 is a critical component in the redistribution of zinc from intracellular stores to the cytoplasm and, as such, is essential for the zinc-induced inhibition of phosphatases, which leads to activation of growth factor receptors. Removal of ZIP7 therefore offers a means through which zinc-induced activation of growth factor receptors may be effectively suppressed and provides a mechanism of targeting multiple growth factor pathways, increasing tumor kill, and preventing further development of resistance in breast cancer.