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

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.

SUBMITTER: Bassey-Archibong BI

PROVIDER: S-EPMC4815049 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Bassey-Archibong B I BI Kwiecien J M JM Milosavljevic S B SB Hallett R M RM Rayner L G A LG Erb M J MJ Crawford-Brown C J CJ Stephenson K B KB Bédard P-A PA Hassell J A JA Daniel J M JM

Oncogenesis 20160321

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 tumori ...[more]

PMID: 26999717

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Project description:There is a major need to better understand the molecular basis of triple negative breast cancer (TNBC) in order to develop effective therapeutic strategies. Using gene expression data from 587 TNBC patients we previously identified six subtypes of the disease, among which a mesenchymal-stem like (MSL) subtype. The MSL subtype has significantly higher expression of the transforming growth factor beta (TGF-?) pathway-associated genes relative to other subtypes, including the TGF-? receptor type III (T?RIII). We hypothesize that T?RIII is tumor promoter in mesenchymal-stem like TNBC cells.Representative MSL cell lines SUM159, MDA-MB-231 and MDA-MB-157 were used to study the roles of T?RIII in the MSL subtype. We stably expressed short hairpin RNAs specific to T?RIII (T?RIII-KD). These cells were then used for xenograft tumor studies in vivo; and migration, invasion, proliferation and three dimensional culture studies in vitro. Furthermore, we utilized human gene expression datasets to examine T?RIII expression patterns across all TNBC subtypes.T?RIII was the most differentially expressed TGF-? signaling gene in the MSL subtype. Silencing T?RIII expression in MSL cell lines significantly decreased cell motility and invasion. In addition, when T?RIII-KD cells were grown in a three dimensional (3D) culture system or nude mice, there was a loss of invasive protrusions and a significant decrease in xenograft tumor growth, respectively. In pursuit of the mechanistic underpinnings for the observed T?RIII-dependent phenotypes, we discovered that integrin-?2 was expressed at higher level in MSL cells after T?RIII-KD. Stable knockdown of integrin-?2 in T?RIII-KD MSL cells rescued the ability of the MSL cells to migrate and invade at the same level as MSL control cells.We have found that T?RIII is required for migration and invasion in vitro and xenograft growth in vivo. We also show that T?RIII-KD elevates expression of integrin-?2, which is required for the reduced migration and invasion, as determined by siRNA knockdown studies of both T?RIII and integrin-?2. Overall, our results indicate a potential mechanism in which T?RIII modulates integrin-?2 expression to effect MSL cell migration, invasion, and tumorigenicity.

Dataset Information

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

Publications

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

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