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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 expression correlates with shorter metastasis-free survival and EMT. (a) Analysis of the publicly available TCGA breast cancer (BCa) data set revealed that high Kaiso expression correlates with ER (−) negativity and TNBC. **P<0.001. (b) Patients from the TCGA (n=977) and the GEO (GSE20685) (n=327) data sets were segregated into Kaiso (ZBTB33)-high, Kaiso-intermediate and Kaiso-low groups based on transcript levels. Kaplan–Meier survival curves revealed a significant negative correlation between high Kaiso expression, overall survival and distant metastasis-free survival in all BCa cases. Statistical significance was determined by log-rank test and P-values are indicated. (c) RT–PCR and immunoblot analysis of control and Kaiso-depleted MDA-231 and Hs578T cells. (d) Phase-contrast images of control and Kaiso-depleted MDA-231 and Hs578T cells. (e) Phase-contrast images of Kaiso-depleted MDA-231 cells transfected with either an empty or mKaiso vector. Scale bar, 100 μM.
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fig1: High Kaiso expression correlates with shorter metastasis-free survival and EMT. (a) Analysis of the publicly available TCGA breast cancer (BCa) data set revealed that high Kaiso expression correlates with ER (−) negativity and TNBC. **P<0.001. (b) Patients from the TCGA (n=977) and the GEO (GSE20685) (n=327) data sets were segregated into Kaiso (ZBTB33)-high, Kaiso-intermediate and Kaiso-low groups based on transcript levels. Kaplan–Meier survival curves revealed a significant negative correlation between high Kaiso expression, overall survival and distant metastasis-free survival in all BCa cases. Statistical significance was determined by log-rank test and P-values are indicated. (c) RT–PCR and immunoblot analysis of control and Kaiso-depleted MDA-231 and Hs578T cells. (d) Phase-contrast images of control and Kaiso-depleted MDA-231 and Hs578T cells. (e) Phase-contrast images of Kaiso-depleted MDA-231 cells transfected with either an empty or mKaiso vector. Scale bar, 100 μM.

Mentions: Kaiso is highly expressed in several TNBC cell lines (our unpublished data) and nuclear Kaiso expression has been linked with EMT and TNBC aggressiveness.20, 29 To determine the clinical relevance of Kaiso (ZBTB33) expression in aggressive BCa, we analyzed The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) (GSE20685) breast cancer data sets. Consistent with an earlier study,29 most high Kaiso-expressing tumors lacked the estrogen receptor. However, the highest and most statistically significant Kaiso expression correlated with TNBC cases (Figure 1a). Importantly, Kaplan–Meier survival curves revealed that patients with high Kaiso-expressing tumors (ZBTB33 high) had a poorer overall survival (log-rank test, P=0.0052) and shorter distant metastasis-free survival (log-rank test, P=0.02) compared with patients with intermediate or low Kaiso-expressing tumors (Figure 1b) in all BCa cases. These findings suggested a clinically relevant role for Kaiso in TNBC.


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 expression correlates with shorter metastasis-free survival and EMT. (a) Analysis of the publicly available TCGA breast cancer (BCa) data set revealed that high Kaiso expression correlates with ER (−) negativity and TNBC. **P<0.001. (b) Patients from the TCGA (n=977) and the GEO (GSE20685) (n=327) data sets were segregated into Kaiso (ZBTB33)-high, Kaiso-intermediate and Kaiso-low groups based on transcript levels. Kaplan–Meier survival curves revealed a significant negative correlation between high Kaiso expression, overall survival and distant metastasis-free survival in all BCa cases. Statistical significance was determined by log-rank test and P-values are indicated. (c) RT–PCR and immunoblot analysis of control and Kaiso-depleted MDA-231 and Hs578T cells. (d) Phase-contrast images of control and Kaiso-depleted MDA-231 and Hs578T cells. (e) Phase-contrast images of Kaiso-depleted MDA-231 cells transfected with either an empty or mKaiso vector. Scale bar, 100 μM.
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Related In: Results  -  Collection

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fig1: High Kaiso expression correlates with shorter metastasis-free survival and EMT. (a) Analysis of the publicly available TCGA breast cancer (BCa) data set revealed that high Kaiso expression correlates with ER (−) negativity and TNBC. **P<0.001. (b) Patients from the TCGA (n=977) and the GEO (GSE20685) (n=327) data sets were segregated into Kaiso (ZBTB33)-high, Kaiso-intermediate and Kaiso-low groups based on transcript levels. Kaplan–Meier survival curves revealed a significant negative correlation between high Kaiso expression, overall survival and distant metastasis-free survival in all BCa cases. Statistical significance was determined by log-rank test and P-values are indicated. (c) RT–PCR and immunoblot analysis of control and Kaiso-depleted MDA-231 and Hs578T cells. (d) Phase-contrast images of control and Kaiso-depleted MDA-231 and Hs578T cells. (e) Phase-contrast images of Kaiso-depleted MDA-231 cells transfected with either an empty or mKaiso vector. Scale bar, 100 μM.
Mentions: Kaiso is highly expressed in several TNBC cell lines (our unpublished data) and nuclear Kaiso expression has been linked with EMT and TNBC aggressiveness.20, 29 To determine the clinical relevance of Kaiso (ZBTB33) expression in aggressive BCa, we analyzed The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) (GSE20685) breast cancer data sets. Consistent with an earlier study,29 most high Kaiso-expressing tumors lacked the estrogen receptor. However, the highest and most statistically significant Kaiso expression correlated with TNBC cases (Figure 1a). Importantly, Kaplan–Meier survival curves revealed that patients with high Kaiso-expressing tumors (ZBTB33 high) had a poorer overall survival (log-rank test, P=0.0052) and shorter distant metastasis-free survival (log-rank test, P=0.02) compared with patients with intermediate or low Kaiso-expressing tumors (Figure 1b) in all BCa cases. These findings suggested a clinically relevant role for Kaiso in TNBC.

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