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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

Potential model of the role of Kaiso in tumor progression and metastasis. (a) TGFβ signaling increases Kaiso expression that in turn promotes TGFβ signaling through increased expression of TGFβR1 and/or TGFβR2. TGFβ and Kaiso then promote EMT through increased expression of Slug, ZEB1 and/or Vimentin. (b) Less aggressive breast cancers exhibit low Kaiso expression, whereas highly metastatic breast tumors display high Kaiso expression, correlating with shorter metastasis-free survival. However, it remains to be determined whether high Kaiso expression occurs before tumor cells become highly aggressive or vice versa.
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fig8: Potential model of the role of Kaiso in tumor progression and metastasis. (a) TGFβ signaling increases Kaiso expression that in turn promotes TGFβ signaling through increased expression of TGFβR1 and/or TGFβR2. TGFβ and Kaiso then promote EMT through increased expression of Slug, ZEB1 and/or Vimentin. (b) Less aggressive breast cancers exhibit low Kaiso expression, whereas highly metastatic breast tumors display high Kaiso expression, correlating with shorter metastasis-free survival. However, it remains to be determined whether high Kaiso expression occurs before tumor cells become highly aggressive or vice versa.

Mentions: Our unexpected finding that TGFβ treatment increased Kaiso expression in breast tumor cells suggests that TGFβ signaling may positively regulate Kaiso expression, and thus form a positive feedback loop that enhances TGFβ-mediated signaling and metastasis (Figure 8a). Intriguingly, Kaiso may itself be required for TGFβ signaling or participate in other pathways implicated in BCa metastasis as overexpression of a kinase-active TGFβR1 in Kaiso-depleted MDA-231 cells was insufficient to rescue their metastatic abilities. Such findings are consistent with our model (Figure 8b), and other studies that have implicated increased Kaiso expression in the aggressiveness and overall survival of BCa patients.20, 29 However, it remains to be determined whether increased TGFβ signaling first induces high Kaiso expression or vice versa.


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)

Potential model of the role of Kaiso in tumor progression and metastasis. (a) TGFβ signaling increases Kaiso expression that in turn promotes TGFβ signaling through increased expression of TGFβR1 and/or TGFβR2. TGFβ and Kaiso then promote EMT through increased expression of Slug, ZEB1 and/or Vimentin. (b) Less aggressive breast cancers exhibit low Kaiso expression, whereas highly metastatic breast tumors display high Kaiso expression, correlating with shorter metastasis-free survival. However, it remains to be determined whether high Kaiso expression occurs before tumor cells become highly aggressive or vice versa.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: Potential model of the role of Kaiso in tumor progression and metastasis. (a) TGFβ signaling increases Kaiso expression that in turn promotes TGFβ signaling through increased expression of TGFβR1 and/or TGFβR2. TGFβ and Kaiso then promote EMT through increased expression of Slug, ZEB1 and/or Vimentin. (b) Less aggressive breast cancers exhibit low Kaiso expression, whereas highly metastatic breast tumors display high Kaiso expression, correlating with shorter metastasis-free survival. However, it remains to be determined whether high Kaiso expression occurs before tumor cells become highly aggressive or vice versa.
Mentions: Our unexpected finding that TGFβ treatment increased Kaiso expression in breast tumor cells suggests that TGFβ signaling may positively regulate Kaiso expression, and thus form a positive feedback loop that enhances TGFβ-mediated signaling and metastasis (Figure 8a). Intriguingly, Kaiso may itself be required for TGFβ signaling or participate in other pathways implicated in BCa metastasis as overexpression of a kinase-active TGFβR1 in Kaiso-depleted MDA-231 cells was insufficient to rescue their metastatic abilities. Such findings are consistent with our model (Figure 8b), and other studies that have implicated increased Kaiso expression in the aggressiveness and overall survival of BCa patients.20, 29 However, it remains to be determined whether increased TGFβ signaling first induces high Kaiso expression or vice versa.

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