Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells.
Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells.
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DOI：
10.1038/oncsis.2016.17
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发表时间：
2016-03-21
期刊：
影响因子：
6.2
通讯作者：
Daniel JM
中科院分区：
文献类型：
--
作者：
Bassey-Archibong BI;Kwiecien JM;Milosavljevic SB;Hallett RM;Rayner LG;Erb MJ;Crawford-Brown CJ;Stephenson KB;Bédard PA;Hassell JA;Daniel JM
三阴性乳腺癌（TNBC）代表高度侵袭性和转移性的乳腺肿瘤的一个子集，并且导致不成比例的乳腺癌相关死亡。一些研究已经假设上皮-间质转化（EMT）程序在TNBC的增加的侵袭性和转移倾向中的作用。虽然EMT对于早期脊椎动物发育和伤口愈合是必不可少的，但它在肿瘤发生期间经常被癌细胞吸收。参与EMT的一个突出的信号传导途径是转化生长因子-β（TGFβ）途径。在这项研究中，我们报告了新的POZ-ZF转录因子Kaiso在TNBC中高度表达，并与较短的无转移生存期相关。值得注意的是，Kaiso表达由TGFβ途径诱导，并且在高度侵袭性乳腺癌细胞系MDA-MB-231（下文称为MDA-231）和Hs 578 T中沉默Kaiso表达，减弱几种EMT相关蛋白（波形蛋白、Slug和ZEB 1）的表达，消除TGFβ信号传导和TGFβ依赖性EMT。此外，Kaiso消耗减弱了小鼠模型中TNBC细胞（MDA-231和Hs 578 T）的转移。尽管Kaiso和TGFβR1高表达与乳腺癌患者的总体生存率差相关，但Kaiso耗竭细胞中激酶活性TGFβR1的过表达不足以恢复这些细胞的转移潜力，表明Kaiso是TGFβ介导的促转移反应的关键下游组分。总的来说，这些发现表明Kaiso在TGFβ信号传导和TNBC转移中起关键作用。
Triple-negative breast cancers (TNBCs) represent a subset of breast tumors that are highly aggressive and metastatic, and are responsible for a disproportionate number of breast cancer-related deaths. Several studies have postulated a role for the epithelial-to-mesenchymal transition (EMT) program in the increased aggressiveness and metastatic propensity of TNBCs. Although EMT is essential for early vertebrate development and wound healing, it is frequently co-opted by cancer cells during tumorigenesis. One prominent signaling pathway involved in EMT is the transforming growth factor-β (TGFβ) pathway. In this study, we report that the novel POZ-ZF transcription factor Kaiso is highly expressed in TNBCs and correlates with a shorter metastasis-free survival. Notably, Kaiso expression is induced by the TGFβ pathway and silencing Kaiso expression in the highly invasive breast cancer cell lines, MDA-MB-231 (hereafter MDA-231) and Hs578T, attenuated the expression of several EMT-associated proteins (Vimentin, Slug and ZEB1), abrogated TGFβ signaling and TGFβ-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGFβR1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGFβR1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGFβ-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGFβ signaling and the metastasis of TNBCs.