Zip6-attenuation promotes epithelial-to-mesenchymal transition in ductal breast tumor (T47D) cells
Zip6-attenuation promotes epithelial-to-mesenchymal transition in ductal breast tumor (T47D) cells
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DOI：
10.1016/j.yexcr.2009.10.011
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发表时间：
2010-02-01
影响因子：
3.7
通讯作者：
Kelleher, Shannon L.
中科院分区：
文献类型：
--
作者：
Lopez, Veronica;Kelleher, Shannon L.
乳腺癌与乳腺组织中锌的过度积聚有关，这种过度积聚被认为是由于锌导入蛋白的过度表达而增强的。Zip6(Liv-1)在雌激素受体阳性(ER+)的乳腺肿瘤中过表达。抗雌激素，如氟维司他，通常用于ER+乳腺癌，因此可能在调节细胞内锌的过度积累方面发挥作用。在此，我们研究了Zip6过表达的生理学相关性以及Zip6在乳腺肿瘤细胞中减弱的后果，以此作为抗雌激素抵抗发生的机制。我们发现，与正常乳腺细胞相比，Zip6的过度表达与肿瘤细胞中显著更高的细胞锌水平有关。Fulvestrant显著减少了肿瘤细胞中的锌蓄积，但对Zip6蛋白丰度没有明显影响。Zip6的衰减显著减少了细胞内的锌库，这与线粒体膜电位(Delta Psi M)增加和细胞凋亡刺激(细胞质细胞色素C释放、caspase-3和-9活性)减少有关。重要的是，细胞凋亡率的减少显著增加了软琼脂中的肿瘤集落形成，并且与E-钙粘附素的表达减少有关。我们的数据表明，抗雌激素治疗调节了锌水平，并重要地证实了Zip6的过度表达不是引发乳腺癌的潜在机制，但实际上可能起到了“肿瘤抑制”的作用。(C)2009 Elsevier Inc.保留所有权利。
Breast cancer is associated with zinc (Zn) hyper-accumulation in breast tissue which is postulated to be potentiated by the over-expression of Zn importing proteins. Zip6 (LIV-1) over-expression has been documented in estrogen receptor-positive (ER+) breast tumors. Anti-estrogens, such as fulvestrant, are typically prescribed for ER+ breast cancer and thus may play a role in modulating cellular Zn hyper-accumulation. Herein, we investigated the physiological relevance of Zip6 overexpression and the consequences of Zip6-attenuation in breast tumor cells as a mechanism in the development of anti-estrogen resistance. We documented that over-expression of Zip6 was associated with significantly higher cellular Zn levels in tumor cells compared with normal breast cells. Fulvestrant significantly reduced Zn accumulation in tumor cells, without robust effects on Zip6 protein abundance. Zip6-attenuation significantly reduced cellular Zn pools, which was associated with increased mitochondrial membrane potential (Delta psi m) and decreased apoptotic stimuli (cytoplasmic cytochrome C release, caspase-3 and -9 activities). Importantly, decreased apoptosis significantly increased tumor colony formation in soft agar and was associated with reduced E-cadherin expression. Our data suggest that anti-estrogen treatment regulates Zn level and importantly verify that Zip6 over-expression is not an underlying mechanism initiating breast cancer, but in fact may play a "tumor-constraining" role. (C) 2009 Elsevier Inc. All rights reserved.