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Kaiso depletion attenuates transforming growth factor-? 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-? (TGF?) 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 TGF? 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 TGF? signaling and TGF?-dependent EMT. Moreover, Kaiso depletion attenuated the metastasis of TNBC cells (MDA-231 and Hs578T) in a mouse model. Although high Kaiso and high TGF?R1 expression is associated with poor overall survival in breast cancer patients, overexpression of a kinase-active TGF?R1 in the Kaiso-depleted cells was insufficient to restore the metastatic potential of these cells, suggesting that Kaiso is a key downstream component of TGF?-mediated pro-metastatic responses. Collectively, these findings suggest a critical role for Kaiso in TGF? 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.

Project description:BackgroundMost breast cancer-related deaths result from metastasis. Understanding the molecular basis of metastasis is needed for the development of effective targeted and preventive strategies. Matrix metalloproteinase-1 (MMP1) plays an important role in brain metastasis (BM) of triple-negative breast cancer (TNBC) by promoting extravasation of cancer cells across the brain endothelium (BE). MMP1 expression is controlled by endogenous microRNAs. Preliminary bioinformatics analysis has revealed that miR-623, known to target the 3'UTR of MMP1, is significantly downregulated in brain metastatic tumors compared to primary BC tumors. However, the involvement of miR-623 in MMP1 upregulation in breast cancer brain metastatic cells (BCBMC) remains unexplored. Here, we investigated the role of miR-623 in MMP1 regulation and its impact on the extravasation of TNBC cells through the BE in vitro.Materials and methodsA loss-and-gain of function method was employed to address the effect of miR-623 modulation on MMP1 expression. MMP1 regulation by miR-623 was investigated by real-time PCR, western blot, luciferase and transwell migration assays using an in vitro human BE model.ResultsOur results confirmed that brain metastatic TNBC cells express lower levels of miR-623 compared with cells having low propensity to spread toward the brain. miR-623 binds to the 3'-untranslated region of MMP1 transcript and downregulates its expression. Restoring miR-623 expression significantly decreased MMP1 expression, preserved the endothelial barrier integrity, and attenuated transmigration of BCBMC through the BE.ConclusionOur study elucidates, for the first time, the crucial role of miR-623 as MMP1 direct regulator in BCBMC and sheds light on miR-623 as a novel therapeutic target that can be exploited to predict and prevent brain metastasis in TNBC. Importantly, the presents study helps in unraveling a brain metastasis-specific microRNA signature in TNBC that can be used as a guide to personalized metastasis prediction and preventive approach with better therapeutic outcome.

Project description:Osteosarcoma is a rare type of bone cancer, and half of the cases affect children and adolescents younger than 20 years of age. Despite intensive efforts to improve both chemotherapeutics and surgical management, the clinical outcome for metastatic osteosarcoma remains poor. Transforming growth factor β (TGF-β) is one of the most abundant growth factors in bones. The TGF-β signaling pathway has complex and contradictory roles in the pathogenesis of human cancers. TGF-β is primarily a tumor suppressor that inhibits proliferation and induces apoptosis of premalignant epithelial cells. In the later stages of cancer progression, however, TGF-β functions as a metastasis promoter by promoting tumor growth, inducing epithelial-mesenchymal transition (EMT), blocking antitumor immune responses, increasing tumor-associated fibrosis, and enhancing angiogenesis. In contrast with the dual effects of TGF-β on carcinoma (epithelial origin) progression, TGF-β seems to mainly have a pro-tumoral effect on sarcomas including osteosarcoma (mesenchymal origin). Many drugs that target TGF-β signaling have been developed: neutralizing antibodies that prevent TGF-β binding to receptor complexes; ligand trap employing recombinant Fc-fusion proteins containing the soluble ectodomain of either type II (TβRII) or the type III receptor ((TβRIII), preventing TGF-β from binding to its receptors; antisense nucleotides that reduce TGF-β expression at the transcriptional/translational level; small molecule inhibitors of serine/threonine kinases of the type I receptor (TβRI) preventing downstream signaling; and vaccines that contain cell lines transfected with TβRII antisense genes, or target furin convertase, resulting in reduced TGF-β signaling. TGF-β antagonists have been shown to have effects on osteosarcoma in vitro and in vivo. One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. Several phase 1/2/3 clinical trials have shown TGF-β antagonists are safe and well tolerated. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.

Dataset Information

Kaiso depletion attenuates transforming growth factor-? 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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