title: Kaiso depletion attenuates transforming growth factor-β signaling and metastatic activity of triple-negative breast cancer cells.
abstract: 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.
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: B I
authors.initials: BI
authors.lastname: Bassey-Archibong
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.|Department of Neurosurgery and Paediatric Neurosurgery, Medical University of Lublin, Lublin, Poland.
authors.forename: J M
authors.initials: JM
authors.lastname: Kwiecien
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: S B
authors.initials: SB
authors.lastname: Milosavljevic
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: R M
authors.initials: RM
authors.lastname: Hallett
authors.affiliation: Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ontario, Canada.
authors.forename: L G A
authors.initials: LG
authors.lastname: Rayner
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Erb
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Crawford-Brown
authors.affiliation: Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: K B
authors.initials: KB
authors.lastname: Stephenson
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: P-A
authors.initials: PA
authors.lastname: Bédard
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: J A
authors.initials: JA
authors.lastname: Hassell
authors.affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: J M
authors.initials: JM
authors.lastname: Daniel