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

• Published in: Oncogenesis (New York, NY) Vol. 5; no. 3; p. e208
• Main Authors: Bassey-Archibong, B I, Kwiecien, J M, Milosavljevic, S B, Hallett, R M, Rayner, L G A, Erb, M J, Crawford-Brown, C J, Stephenson, K B, Bédard, P-A, Hassell, J A, Daniel, J M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-03-2016; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/51; 13/89; 14; 38; 631/67/1347; 631/80/86; 64; 64/60; 82; Apoptosis; Cell Biology; Human Genetics; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original; original-article
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/oncsis.2016.17

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.