High motility of triple-negative breast cancer cells is due to repression of plakoglobin gene by metastasis modulator protein SLUG.
ABSTRACT One of highly pathogenic breast cancer cell types are the triple negative (negative in the expression of estrogen, progesterone, and ERBB2 receptors) breast cancer cells. These cells are highly motile and metastatic and are characterized by high levels of the metastasis regulator protein SLUG. Using isogenic breast cancer cell systems we have shown here that high motility of these cells is directly correlated with the levels of the SLUG in these cells. Because epithelial/mesenchymal cell motility is known to be negatively regulated by the catenin protein plakoglobin, we postulated that the transcriptional repressor protein SLUG increases the motility of the aggressive breast cancer cells through the knockdown of the transcription of the plakoglobin gene. We found that SLUG inhibits the expression of plakoglobin gene directly in these cells. Overexpression of SLUG in the SLUG-deficient cancer cells significantly decreased the levels of mRNA and protein of plakoglobin. On the contrary, knockdown of SLUG in SLUG-high cancer cells elevated the levels of plakoglobin. Blocking of SLUG function with a double-stranded DNA decoy that competes with the E2-box binding of SLUG also increased the levels of plakoglobin mRNA, protein, and promoter activity in the SLUG-high triple negative breast cancer cells. Overexpression of SLUG in the SLUG-deficient cells elevated the motility of these cells. Knockdown of plakoglobin in these low motility non-invasive breast cancer cells rearranged the actin filaments and increased the motility of these cells. Forced expression of plakoglobin in SLUG-high cells had the reverse effects on cellular motility. This study thus implicates SLUG-induced repression of plakoglobin as a motility determinant in highly disseminating breast cancer.
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ABSTRACT: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths among female population worldwide. Metastases are the common cause of morbidity and mortality in breast cancer and can remain latent for several years after surgical removal of the primary tumour. Thus, the identification and functional characterisation of molecular factors that promote oncogenic signalling in mammary tumour development and progression could provide new entry points for designing targeted therapeutic strategies for metastatic breast cancer. In the present study, we investigated the expression of proteins involved in cell signalling (growth hormone receptor (GHR) and NEDD9) and cell-cell adhesion (plakoglobin) in epithelial and stromal compartments of primary ductal invasive breast carcinomas and their axillary lymph node metastases versus non-metastatic tumours. Obtained data revealed remarkable increase in the expression levels of GHR and NEDD9 proteins in both epithelial and stromal components of axillary lymph node metastases in comparison with those of non-metastatic tumours, suggesting that the expression of these two proteins may provide biomarkers for tumour aggressiveness.Tumor Biology 03/2014; · 2.52 Impact Factor
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ABSTRACT: Plakoglobin (γ-catenin) is a homolog of β-catenin with dual adhesive and signaling functions. Plakoglobin participates in cell-cell adhesion as a component of the adherens junction and desmosomes whereas its signaling function is mediated by its interactions with various intracellular protein partners. To determine the role of plakoglobin during tumorigenesis and metastasis, we expressed plakoglobin in the human tongue squamous cell carcinoma (SCC9) cells and compared the mRNA profiles of parental SCC9 cells and their plakoglobin-expressing transfectants (SCC9-PG). We observed that the mRNA levels of SATB1, the oncogenic chromatin remodeling factor, were decreased approximately 3-fold in SCC9-PG cells compared to parental SCC9 cells. Here, we showed that plakoglobin decreased levels of SATB1 mRNA and protein in SCC9-PG cells and that plakoglobin and p53 associated with the SATB1 promoter. Plakoglobin expression also resulted in decreased SATB1 promoter activity. These results were confirmed following plakoglobin expression in the very low plakoglobin expressing and invasive mammary carcinoma cell line MDA-MB-231 cells (MDA-231-PG). In addition, knockdown of endogenous plakoglobin in the non-invasive mammary carcinoma MCF-7 cells (MCF-7-shPG) resulted in increased SATB1 mRNA and protein. Plakoglobin expression also resulted in increased mRNA and protein levels of the metastasis suppressor Nm23-H1, a SATB1 target gene. Furthermore, the levels of various SATB1 target genes involved in tumorigenesis and metastasis were altered in MCF-7-shPG cells relative to parental MCF-7 cells. Finally, plakoglobin expression resulted in decreased in vitro proliferation, migration and invasion in different carcinoma cell lines. Together with the results of our previous studies, the data suggests that plakoglobin suppresses tumorigenesis and metastasis through the regulation of genes involved in these processes.PLoS ONE 01/2013; 8(11):e78388. · 3.53 Impact Factor
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ABSTRACT: Human PPPDE peptidase domain-containing protein 1 (PPPDE1) is a recently identified protein; however, its exact functions remain unclear. In our previous study, the PPPDE1 protein was found to be decreased in certain cancer tissues. In the present study, a total of 96 pancreatic ductal carcinoma tissue samples and 31 normal tissues samples were assessed to investigate the distribution of plakoglobin and β-catenin under the conditions of various PPPDE1 expression levels by means of immunohistochemistry. Generally, the staining of PPPDE1 was strong in normal tissues, but weak in cancer tissues. Plakoglobin was mainly distributed along the membrane and cytoplasm border in normal cells, but was less evident in the membranes of cancer cells. In particular, a greater percentage of cells exhibited low membrane plakoglobin expression in cancer tissue with low PPPDE1 expression (PPPDE1-low cancer) compared with that in cancer tissue with high PPPDE1 expression (PPPDE1-high cancer). The distribution of β-catenin in normal tissues was similar to that of plakoglobin. However, β-catenin was peculiarly prone to invade nucleus in PPPDE1-low cancer compared with PPPDE1-high cancer. Our data suggested potential links between PPPDE1 expression and the distribution of plakoglobin and β-catenin in pancreatic ductal adenocarcinoma, providing insights into the role of PPPDE1 in the progression of pancreatic cancer.Oncology letters 09/2014; 8(3):1229-1233. · 0.24 Impact Factor