Dominant-negative E-cadherin inhibits the invasiveness of inflammatory breast cancer cells in vitro.
ABSTRACT 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.
SourceAvailable from: Peter van Dam[Show abstract] [Hide abstract]
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 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: To analyze correlation between immunoexpression of E-cadherin and efficacy of first line platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma. The expression of E-cadherin was analyzed immunohistochemically in formalin-fixed, paraffin-embedded samples from 98 patients with advanced-stage high-grade serous ovarian cancer and related to clinical features (stage according to the International Federation of Gynecology and Obstetrics (FIGO) and residual tumors after initial cytoreductive surgery), response to platinum-based chemotherapy (according to Response Evaluation Criteria in Solid tumors (RECIST 1.1 criteria)), platinum sensitivity (according to platinum free interval (PFI) as platinum-refractory, platinum-resistant and platinum-sensitive) and patients progression free survival (PFS) and overall survival (OS). E-cadherin immunostaining was positive in 74 and negative in 24 serous ovarian carcinomas. E-cadherin immunoreactivity was not associated with FIGO stage, residual tumor after initial cytoreductive surgery and number of chemotherapy cycles. Positive E-cadherin expression predict significantly better response to first line platinum-based chemotherapy (p < 0.001) and platinum sensitivity (p < 0.001). Moreover, positive E-cadherin expression predict significantly longer PFS (p < 0.001) and OS (p < 0.001). The multivariate analysis for OS showed that positive E-cadherin expression is predictor to platinum sensitivity (p < 0.001) and longer OS (p = 0.01). Positive E-cadherin expression seems to be a predictor of better response to first line platinum-based chemotherapy, platinum sensitivity and favorable clinical outcome in patients with advanced-stage serous ovarian cancer. Negative E-cadherin expression was shown to be significant, independent predictor of poorer PFS and OS. E-cadherin as a marker has predictive and prognostic value.Pathology & Oncology Research 08/2014; 21(2). DOI:10.1007/s12253-014-9827-1 · 1.81 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Inflammatory breast cancer (IBC) is the most lethal variant of locally advanced breast cancer. Although recognized as a distinct clinical entity, there have been few advances in the development of pre-clinical models of IBC, and a lack of IBC-specific therapeutic targets translated into clinical utility to increase overall survival, which is currently 40 % at three years. By use of newly developed pre-clinical models of IBC and patient tumor tissues, E-cadherin, anaplastic lymphoma kinase (ALK), and HSP90 have been identified as targets relevant to IBC that are matched by therapeutics that are either currently in clinical trials or will be tested in clinical trials within the next year. These exciting results illustrate the advances that have been made in recent years in defining the molecular basis of IBC as a distinct disease and the significant strides made in identifying more effective strategies for treatment of patients with IBC.Current Breast Cancer Reports 12/2012; 4(4). DOI:10.1007/s12609-012-0087-3