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

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- (TGF) 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 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 signaling and TGF-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGFR1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGFR1 in the Kaiso-depleted cells was insufcient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGF-mediated pro-metastatic responses. Collectively, these ndings suggest a critical role for Kaiso in TGF signaling and the metastasis of TNBCs.