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

Bassey-Archibong BI, Kwiecien JM, Milosavljevic SB, Hallett RM, Rayner LG, Erb MJ, Crawford-Brown CJ, Stephenson KB, Bédard PA, Hassell JA, Daniel JM - Oncogenesis (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.

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.

No MeSH data available.


Related in: MedlinePlus

Re-expression of a constitutively active TGFβR1 in Kaiso-depleted cells is insufficient to restore breast cancer metastasis. (a) Overexpression of a constitutively active TGFβR1 (TR1204D) in Kaiso-depleted cells restores TGFβ signaling as evidenced by increased levels of p-Smad2 and p-Akt. (b) Hematoxylin and eosin (H&E) staining shows that overexpression of kinase-active TGFβR1 in Kaiso-depleted cells did not restore the metastatic capabilities of the cells. Representative images are shown. β-Actin serves as a loading control.
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fig7: Re-expression of a constitutively active TGFβR1 in Kaiso-depleted cells is insufficient to restore breast cancer metastasis. (a) Overexpression of a constitutively active TGFβR1 (TR1204D) in Kaiso-depleted cells restores TGFβ signaling as evidenced by increased levels of p-Smad2 and p-Akt. (b) Hematoxylin and eosin (H&E) staining shows that overexpression of kinase-active TGFβR1 in Kaiso-depleted cells did not restore the metastatic capabilities of the cells. Representative images are shown. β-Actin serves as a loading control.

Mentions: Based on the above findings, we questioned whether restoration of TGFβ signaling in Kaiso-depleted cells would restore their metastatic abilities. To address this, we overexpressed a constitutively kinase-active TGFβR1 (TRI204D) in Kaiso-depleted MDA-231 and Hs578T cells. TβRI204D overexpression in Kaiso-depleted cells restored TGFβ signaling as evidenced by increased p-Smad2 and other non-Smad proteins (pAkt) compared with MDA-231-sh-K cells (Figure 7a). Remarkably, although TRI204D overexpression restored TGFβ signaling, it was insufficient to restore the metastatic potential of the Kaiso-depleted cells (compare with metastatic foci generated by MDA-231-Ctrl cells in the lungs of injected mice) (Figure 7b). This suggested that Kaiso expression is important for TGFβ-mediated breast tumor metastasis.


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

Bassey-Archibong BI, Kwiecien JM, Milosavljevic SB, Hallett RM, Rayner LG, Erb MJ, Crawford-Brown CJ, Stephenson KB, Bédard PA, Hassell JA, Daniel JM - Oncogenesis (2016)

Re-expression of a constitutively active TGFβR1 in Kaiso-depleted cells is insufficient to restore breast cancer metastasis. (a) Overexpression of a constitutively active TGFβR1 (TR1204D) in Kaiso-depleted cells restores TGFβ signaling as evidenced by increased levels of p-Smad2 and p-Akt. (b) Hematoxylin and eosin (H&E) staining shows that overexpression of kinase-active TGFβR1 in Kaiso-depleted cells did not restore the metastatic capabilities of the cells. Representative images are shown. β-Actin serves as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4815049&req=5

fig7: Re-expression of a constitutively active TGFβR1 in Kaiso-depleted cells is insufficient to restore breast cancer metastasis. (a) Overexpression of a constitutively active TGFβR1 (TR1204D) in Kaiso-depleted cells restores TGFβ signaling as evidenced by increased levels of p-Smad2 and p-Akt. (b) Hematoxylin and eosin (H&E) staining shows that overexpression of kinase-active TGFβR1 in Kaiso-depleted cells did not restore the metastatic capabilities of the cells. Representative images are shown. β-Actin serves as a loading control.
Mentions: Based on the above findings, we questioned whether restoration of TGFβ signaling in Kaiso-depleted cells would restore their metastatic abilities. To address this, we overexpressed a constitutively kinase-active TGFβR1 (TRI204D) in Kaiso-depleted MDA-231 and Hs578T cells. TβRI204D overexpression in Kaiso-depleted cells restored TGFβ signaling as evidenced by increased p-Smad2 and other non-Smad proteins (pAkt) compared with MDA-231-sh-K cells (Figure 7a). Remarkably, although TRI204D overexpression restored TGFβ signaling, it was insufficient to restore the metastatic potential of the Kaiso-depleted cells (compare with metastatic foci generated by MDA-231-Ctrl cells in the lungs of injected mice) (Figure 7b). This suggested that Kaiso expression is important for TGFβ-mediated breast tumor metastasis.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McMaster University, Hamilton, Ontario, Canada.

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.

No MeSH data available.


Related in: MedlinePlus