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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

High Kaiso and TGFβR1 expression correlates with poor prognosis in breast cancer patients. (a) Kaplan–Meier survival curves show that high Kaiso and TGFβR1 expression correlates negatively with overall survival in the TCGA breast cancer data set. (b) High Kaiso and TGFβR2 expression does not correlate with overall survival in the TCGA breast cancer data set. Statistical significance was determined by log-rank test and P-values are indicated.
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fig6: High Kaiso and TGFβR1 expression correlates with poor prognosis in breast cancer patients. (a) Kaplan–Meier survival curves show that high Kaiso and TGFβR1 expression correlates negatively with overall survival in the TCGA breast cancer data set. (b) High Kaiso and TGFβR2 expression does not correlate with overall survival in the TCGA breast cancer data set. Statistical significance was determined by log-rank test and P-values are indicated.

Mentions: As the TGFβ pathway is highly implicated in BCa metastasis, we utilized the TCGA BCa dataset and correlated the expression levels of Kaiso, TGFβR1 or TGFβR2 with BCa survival. Consistent with Chen et al.,44 high TGFβR1 (Supplementary Figure 6) but not high TGFβR2 expression (data not shown) correlated with poor prognosis in BCa patients, although not significantly. Remarkably, increased Kaiso and TGFβR1 expression, but not increased Kaiso and TGFβR2 expression, correlated significantly with poor overall survival in BCa patients (Figures 6a and b). Kaiso may thus drive metastasis through TGFβR1 but not TGFβR2.


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)

High Kaiso and TGFβR1 expression correlates with poor prognosis in breast cancer patients. (a) Kaplan–Meier survival curves show that high Kaiso and TGFβR1 expression correlates negatively with overall survival in the TCGA breast cancer data set. (b) High Kaiso and TGFβR2 expression does not correlate with overall survival in the TCGA breast cancer data set. Statistical significance was determined by log-rank test and P-values are indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: High Kaiso and TGFβR1 expression correlates with poor prognosis in breast cancer patients. (a) Kaplan–Meier survival curves show that high Kaiso and TGFβR1 expression correlates negatively with overall survival in the TCGA breast cancer data set. (b) High Kaiso and TGFβR2 expression does not correlate with overall survival in the TCGA breast cancer data set. Statistical significance was determined by log-rank test and P-values are indicated.
Mentions: As the TGFβ pathway is highly implicated in BCa metastasis, we utilized the TCGA BCa dataset and correlated the expression levels of Kaiso, TGFβR1 or TGFβR2 with BCa survival. Consistent with Chen et al.,44 high TGFβR1 (Supplementary Figure 6) but not high TGFβR2 expression (data not shown) correlated with poor prognosis in BCa patients, although not significantly. Remarkably, increased Kaiso and TGFβR1 expression, but not increased Kaiso and TGFβR2 expression, correlated significantly with poor overall survival in BCa patients (Figures 6a and b). Kaiso may thus drive metastasis through TGFβR1 but not TGFβR2.

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