Dong, H. M. et al. Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro. J. Cancer Res. Clin. Oncol. 133, 83-92

Department of Breast Surgery, Breast Cancer Institute, Cancer Hospital/Cancer Institute, Fudan University, 270 Dong'An Road, 200032, Shanghai, People's Republic of China.
Journal of Cancer Research and Clinical Oncology (Impact Factor: 3.08). 03/2007; 133(2):83-92. DOI: 10.1007/s00432-006-0140-6
Source: PubMed


E-cadherin is a transmembrane glycoprotein which mediates epithelial cell-to-cell adhesion function as a tumor suppressor and frequently loss of expression in a wide spectrum of human cancer. However, recent studies demonstrated that E-cadherin was always over-expressed in inflammatory breast cancer (IBC) specimen and cell lines, which is a clinical extreme malignancy of breast cancer. It is hypothesized that the gain and not the loss of the E-cadherin axis contributes to the IBC unique phenotype. To test this assumption, we generated dominant negative mutant E-cadherin high-expression inflammatory breast cancer cells by introduced dominant negative mutant E-cadherin (H-2kd-E-cad) cDNA into human IBC SUM149 cells. Our studies demonstrated that the ability of invasion of SUM149 cells was significantly inhibited by H-2kd-E-cad via down-regulation of MMP-1 and MMP-9 expression. The underlying signal pathway of MAPK phosphorylated Erk 1/2(P44/42) in H-2kd-E-cad-transfected SUM149 cells was significantly down-regulated compared to parental and mock contrast. Our studies provided further functional evidence as the gain of E-cadherin expression dedicated to the IBC malignant phenotype and the blockage of MAPK/Erk activation maybe a promising therapeutic target.

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    • "In this context, we observed that EMT is not more pronounced in IBC as compared to non-IBC breast cancer samples (data not shown). Studies on the SUM149 IBC cell line actually demonstrated that the invasive nature of IBC tumour cells critically depends on the overexpression of functional E-Cadherin and the influence thereof on MMP1 and MMP9 expression [64]. Another intriguing observation, made by Giampieri and colleagues [65], suggests that reduced levels of TGFβ, a negative regulator of E-Cadherin through SNAIL and TWIST [66]–[67], prevent tumour cells from moving individually but do not inhibit cells moving collectively. "
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    ABSTRACT: Metastases remain the primary cause of cancer-related death. The acquisition of invasive tumour cell behaviour is thought to be a cornerstone of the metastatic cascade. Therefore, gene signatures related to invasiveness could aid in stratifying patients according to their prognostic profile. In the present study we aimed at identifying an invasiveness gene signature and investigated its biological relevance in breast cancer. We collected a set of published gene signatures related to cell motility and invasion. Using this collection, we identified 16 genes that were represented at a higher frequency than observed by coincidence, hereafter named the core invasiveness gene signature. Principal component analysis showed that these overrepresented genes were able to segregate invasive and non-invasive breast cancer cell lines, outperforming sets of 16 randomly selected genes (all P<0.001). When applied onto additional data sets, the expression of the core invasiveness gene signature was significantly elevated in cell lines forced to undergo epithelial-mesenchymal transition. The link between core invasiveness gene expression and epithelial-mesenchymal transition was also confirmed in a dataset consisting of 2420 human breast cancer samples. Univariate and multivariate Cox regression analysis demonstrated that CIG expression is not associated with a shorter distant metastasis free survival interval (HR = 0.956, 95%C.I. = 0.896-1.019, P = 0.186). These data demonstrate that we have identified a set of core invasiveness genes, the expression of which is associated with epithelial-mesenchymal transition in breast cancer cell lines and in human tissue samples. Despite the connection between epithelial-mesenchymal transition and invasive tumour cell behaviour, we were unable to demonstrate a link between the core invasiveness gene signature and enhanced metastatic potential.
    PLoS ONE 02/2014; 9(2):e89262. DOI:10.1371/journal.pone.0089262 · 3.23 Impact Factor
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    • "Paradoxically, E-cadherin over-expression in IBC contributes to disease aggressiveness and low survival rate [8] since, E-cadherin expression by IBC carcinoma cells allows cell to cell adhesion and the formation of tumor emboli within the lymphatic vessels [10,11]. Moreover, the process of invasion and dissemination of IBC tumor emboli is mediated by expression of E-cadherin and the activity of matrix metalloproteinases (MMP-1 and MMP-9) [12]. E-cadherin has also been reported to be involved in different cellular biological processes including cell growth [13] and differentiation [14]. "
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    ABSTRACT: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer characterized by invasion of carcinoma cells into dermal lymphatic vessels where they form tumor emboli over expressing adhesion molecule E-cadherin. Although invasion and metastasis are dynamic processes controlled by complex interaction between tumor cells and microenvironment the mechanisms by which soluble mediators may regulate motility and invasion of IBC cells are poorly understood. The present study investigated the effect of media conditioned by human monocytes U937 secreted cytokines, chemokines and growth factors on the expression of adhesion molecules E-cadherin and fibronectin of human IBC cell line SUM149. Furthermore, cytokines signaling pathway involved were also identified. U937 secreted cytokines, chemokines and growth factors were characterized by cytokine antibody array. The major U937 secreted cytokines/chemokines were interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1/CCL2). When SUM149 cells were seeded in three dimensional (3D) models with media conditioned by U937 secreted cytokines, chemokines and growth factors; results showed: 1) changes in the morphology of IBC cells from epithelial to migratory spindle shape branched like structures; 2) Over-expression of adhesion molecule fibronectin and not E-cadherin. Further analysis revealed that over-expression of fibronectin may be mediated by IL-8 via PI3K/Akt signaling pathway. The present results suggested that cytokines secreted by human monocytes may promote chemotactic migration and spreading of IBC cell lines. Results also indicated that IL-8 the major secreted cytokine by U937 cells may play essential role in fibronectin expression by SUM149 cells via interaction with IL-8 specific receptors and stimulation of PI3K/Akt signaling pathway.
    Cell Communication and Signaling 02/2012; 10(1):3. DOI:10.1186/1478-811X-10-3 · 3.38 Impact Factor
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    • "As GLI1 has been observed to promote cell migration and invasion in other cancer cell types (Das et al, 2009; Lo et al, 2009), including non- IBC breast cancer cell lines (Kameda et al, 2009; Souzaki et al, 2011), we were interested to determine if it has a role in the invasive potential of SUM149 and rSUM149 cells. Further, IBC is unusual in that it is an aggressive type of breast cancer that maintains strong E-cadherin expression (Kleer et al, 2001; Colpaert et al, 2003; Dong et al, 2007). We wanted to investigate whether the high levels of GLI1 in SUM149 cells have a role in its unique migratory phenotype. "
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    ABSTRACT: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients. The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays. Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement. Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.
    British Journal of Cancer 05/2011; 104(10):1575-86. DOI:10.1038/bjc.2011.133 · 4.84 Impact Factor
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