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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

Kaiso depletion inhibits breast tumor cell metastasis to the lungs and liver. (a i–vi) Hematoxylin and eosin (H&E) staining of murine lungs and liver revealed that control MDA-231 xenografts formed extensive metastases in lungs (i) and liver (iii), whereas control Hs578T xenografts formed moderate metastases that were limited to the lungs (v) of immune-deficient mice. In contrast, Kaiso-depleted MDA-231 xenografts formed very few metastases in the lungs (ii), and no metastases in the liver (iv) of immune-deficient mice. Kaiso-depleted Hs578T xenografts also formed negligible metastases in the lung (v). (b) H&E images showing extensive metastases of control MDA-231 (i) and control Hs578T (iii) in the lungs of NSG mice after tail vein injections compared with few metastases formed by Kaiso-depleted MDA-231 (ii) and Hs578T cells (iv). Scale bar, 1000 μm. Representative images are shown.
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fig2: Kaiso depletion inhibits breast tumor cell metastasis to the lungs and liver. (a i–vi) Hematoxylin and eosin (H&E) staining of murine lungs and liver revealed that control MDA-231 xenografts formed extensive metastases in lungs (i) and liver (iii), whereas control Hs578T xenografts formed moderate metastases that were limited to the lungs (v) of immune-deficient mice. In contrast, Kaiso-depleted MDA-231 xenografts formed very few metastases in the lungs (ii), and no metastases in the liver (iv) of immune-deficient mice. Kaiso-depleted Hs578T xenografts also formed negligible metastases in the lung (v). (b) H&E images showing extensive metastases of control MDA-231 (i) and control Hs578T (iii) in the lungs of NSG mice after tail vein injections compared with few metastases formed by Kaiso-depleted MDA-231 (ii) and Hs578T cells (iv). Scale bar, 1000 μm. Representative images are shown.

Mentions: The link of Kaiso to distant metastasis-free survival in BCa patients and EMT (Figure 1)19, 20 led us to question whether Kaiso was essential for TNBC dissemination. Thus, we investigated the effect of Kaiso depletion on TNBC cell metastasis in a mouse model where Kaiso-depleted MDA-231 and Hs578T cells were injected subcutaneously into the mammary fat pads of immuno-compromised mice and allowed to form tumors. In support of our hypothesis, we found that Kaiso-depleted MDA-231 cells exhibited only a few small metastatic foci in the lungs (Figure 2a ii), but no detectable metastases in the liver (Figure 2a iv) or other organs (data not shown) in all xenografted mice (n=9). In contrast, MDA-231 control-injected mice exhibited extensive metastases to the lungs and liver (n=6; Figure 2a i and -iii) as previously shown.32, 33 Similarly, control Hs578T cells exhibited modest metastases that were limited to the lungs of all xenografted mice (n=7; Figure 2a v) compared with Kaiso-depleted Hs578T injected mice that displayed very few metastatic foci in the lungs (n=7; Figure 2a vi). Similar results were obtained in experimental lung metastasis (tail vein injections) studies; control MDA-231 (n=5) and Hs578T (n=5) cells formed large and multiple foci in the lungs of all injected mice (Figure 2b i and iii), whereas Kaiso-depleted MDA-231 (n=5) and Hs578T cells (n=5) formed few foci in the lungs of injected mice (Figure 2b ii and iv). Collectively, these findings highlight for the first time the importance of Kaiso expression on the metastasis of TNBC cells.


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)

Kaiso depletion inhibits breast tumor cell metastasis to the lungs and liver. (a i–vi) Hematoxylin and eosin (H&E) staining of murine lungs and liver revealed that control MDA-231 xenografts formed extensive metastases in lungs (i) and liver (iii), whereas control Hs578T xenografts formed moderate metastases that were limited to the lungs (v) of immune-deficient mice. In contrast, Kaiso-depleted MDA-231 xenografts formed very few metastases in the lungs (ii), and no metastases in the liver (iv) of immune-deficient mice. Kaiso-depleted Hs578T xenografts also formed negligible metastases in the lung (v). (b) H&E images showing extensive metastases of control MDA-231 (i) and control Hs578T (iii) in the lungs of NSG mice after tail vein injections compared with few metastases formed by Kaiso-depleted MDA-231 (ii) and Hs578T cells (iv). Scale bar, 1000 μm. Representative images are shown.
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fig2: Kaiso depletion inhibits breast tumor cell metastasis to the lungs and liver. (a i–vi) Hematoxylin and eosin (H&E) staining of murine lungs and liver revealed that control MDA-231 xenografts formed extensive metastases in lungs (i) and liver (iii), whereas control Hs578T xenografts formed moderate metastases that were limited to the lungs (v) of immune-deficient mice. In contrast, Kaiso-depleted MDA-231 xenografts formed very few metastases in the lungs (ii), and no metastases in the liver (iv) of immune-deficient mice. Kaiso-depleted Hs578T xenografts also formed negligible metastases in the lung (v). (b) H&E images showing extensive metastases of control MDA-231 (i) and control Hs578T (iii) in the lungs of NSG mice after tail vein injections compared with few metastases formed by Kaiso-depleted MDA-231 (ii) and Hs578T cells (iv). Scale bar, 1000 μm. Representative images are shown.
Mentions: The link of Kaiso to distant metastasis-free survival in BCa patients and EMT (Figure 1)19, 20 led us to question whether Kaiso was essential for TNBC dissemination. Thus, we investigated the effect of Kaiso depletion on TNBC cell metastasis in a mouse model where Kaiso-depleted MDA-231 and Hs578T cells were injected subcutaneously into the mammary fat pads of immuno-compromised mice and allowed to form tumors. In support of our hypothesis, we found that Kaiso-depleted MDA-231 cells exhibited only a few small metastatic foci in the lungs (Figure 2a ii), but no detectable metastases in the liver (Figure 2a iv) or other organs (data not shown) in all xenografted mice (n=9). In contrast, MDA-231 control-injected mice exhibited extensive metastases to the lungs and liver (n=6; Figure 2a i and -iii) as previously shown.32, 33 Similarly, control Hs578T cells exhibited modest metastases that were limited to the lungs of all xenografted mice (n=7; Figure 2a v) compared with Kaiso-depleted Hs578T injected mice that displayed very few metastatic foci in the lungs (n=7; Figure 2a vi). Similar results were obtained in experimental lung metastasis (tail vein injections) studies; control MDA-231 (n=5) and Hs578T (n=5) cells formed large and multiple foci in the lungs of all injected mice (Figure 2b i and iii), whereas Kaiso-depleted MDA-231 (n=5) and Hs578T cells (n=5) formed few foci in the lungs of injected mice (Figure 2b ii and iv). Collectively, these findings highlight for the first time the importance of Kaiso expression on the metastasis of TNBC cells.

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