Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells

被引:32
作者
Bassey-Archibong, B. I. [1 ]
Kwiecien, J. M. [2 ,3 ]
Milosavljevic, S. B. [1 ]
Hallett, R. M. [4 ]
Rayner, L. G. A. [5 ]
Erb, M. J. [1 ]
Crawford-Brown, C. J. [1 ]
Stephenson, K. B. [6 ]
Bedard, P-A [1 ]
Hassell, J. A. [4 ]
Daniel, J. M. [1 ]
机构
[1] McMaster Univ, Dept Biol, LSB 331,1280 Main St West, Hamilton, ON L8S 4K1, Canada
[2] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada
[3] Med Univ Lublin, Dept Neurosurg & Paediat Neurosurg, Lublin, Poland
[4] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada
[5] McMaster Univ, Dept Psychol Neurosci & Behav, Hamilton, ON, Canada
[6] Ottawa Hosp, Res Inst, Ctr Innovat Canc Res, Ottawa, ON, Canada
基金
加拿大健康研究院; 加拿大自然科学与工程研究理事会;
关键词
TGF-BETA; TRANSCRIPTION FACTOR; PATHWAY; EXPRESSION; PHENOTYPE; VIMENTIN; PROMOTES; RECEPTOR; INVASIVENESS; ASSOCIATION;
D O I
10.1038/oncsis.2016.17
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 epithelialto-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-beta (TGF beta) 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 TGF beta 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 TGF beta signaling and TGF beta-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGF beta R1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGF beta R1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGF beta-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGF beta signaling and the metastasis of TNBCs.
引用
收藏
页码:e208 / e208
页数:10
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