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ABSTRACT: Rho-like small GTPases, including RhoA, Rac1 and Cdc42, are crucial for the regulation of a large variety of biological processes such as the cytoskeletal organization and gene transcription. The activities of Rho GTPases are predominantly controlled by guanine nucleotide exchange factors (GEFs), which activate GTPases by catalyzing the exchange of bound GDP for GTP. Earlier, we have identified the Tiam1 gene as an invasion-inducing gene that encodes a specific activator (GEF) of the Rac GTPase. We found that Tiam1-mediated Rac signaling functions in various aspects of tumorigenicity including the formation and progression of Ras-induced skin tumors and Wnt-induced intestinal tumors. Here, we further distinguish the oncogenic pathways that depend on Tiam1 signaling in the mammary gland.
We crossed Tiam1 knockout mice with MMTV-c-myc and MMTV-c-neu transgenic mice, in which the expression of both oncogenes is targeted to the mammary gland leading to mammary tumorigenesis.
We found Tiam1 important for Neu-induced tumor formation and progression but not for Myc-induced tumors. Tiam1-deficiency delayed Neu-induced tumor initiation and reduced metastasis but had no effect on the growth of the MMTV-c-neu tumors.
Our data indicate that the Rac activator Tiam1 contributes to tumorigenicity induced by specific oncogenic signaling pathways only.
Journal of Cancer Research and Clinical Oncology 08/2008; 135(1):69-80. · 2.56 Impact Factor
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ABSTRACT: In this study, we examined the role of the E-cadherin-repressed gene human Nanos1 (hNanos1) in tumor invasion process. First, our in vivo study revealed that hNanos1 mRNAs were overexpressed in invasive lung carcinomas. Moreover, hNanos1 was co-localized with MT1-MMP (membrane type 1-matrix metalloproteinase) in E-cadherin-negative invasive lung tumor clusters. Using an inducible Tet-on system, we showed that induction of hNanos1 expression in DLD1 cells increased their migratory and invasive abilities in a three-dimensional migration and in a modified Boyden chamber assay. Accordingly, we demonstrated that hNanos1 upregulated MT1-MMP expression at the mRNA and protein levels. Inversely, using an RNA interference strategy to inhibit hNanos1 expression in invasive Hs578T, BT549 and BZR cancer cells, we observed a downregulation of MT1-MMP mRNA and protein and concomitantly a decrease of the invasive capacities of tumor cells in a modified Boyden chamber assay. Taken together, our results demonstrate that hNanos1, by regulating MT1-MMP expression, plays an important role in the acquisition of invasive properties by epithelial tumor cells.
Oncogene 07/2008; 27(26):3692-9. · 6.37 Impact Factor
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ABSTRACT: The presence of a functional E-cadherin/catenin cell-cell adhesion complex is a prerequisite for normal development and maintenance of epithelial structures in the mammalian body. This implies that the acquisition of molecular abnormalities that disturb the expression or function of this complex is related to the development and progression of most, if not all, epithelial cell-derived tumors, i.e. carcinomas. E-cadherin downregulation is indeed correlated with malignancy parameters such as tumor progression, loss of differentiation, invasion and metastasis, and hence poor prognosis. Moreover, E-cadherin has been shown to be a potent invasion suppressor as well as a tumor suppressor. Disturbed expression profiles of the E-cadherin/catenin complex have been demonstrated in histological sections of many human tumor types. In different kinds of carcinomas, biallelic downregulation of the E-cadherin gene, resulting in tumor-restricted decrease or even complete loss of E-cadherin expression, appears to be caused by a variety of inactivation mechanisms. Gene deletion due to loss of heterozygosity of the CDH1 locus on 16q22.1 frequently occurs in many carcinoma types. However, somatic inactivating mutations resulting in aberrant E-cadherin expression by loss of both wild-type alleles is rare and restricted to only a few cancer types. A majority of carcinomas thus seems to show deregulated E-cadherin expression by other mechanisms. The present evidence proposes transcriptional repression as a powerful and recurrent molecular mechanism for silencing E-cadherin expression. The predominant mechanisms emerging in most carcinomas are hypermethylation of the E-cadherin promoter and expression of transrepressor molecules such as SIP1, Snail, and Slug that bind sequence elements in the proximal E-cadherin promoter. Interestingly, complex differential expression of other cadherins seems to be associated with loss of E-cadherin and to reinforce effects of this loss on tumor progression. Multiple agents can upregulate and stabilize the E-cadherin/catenin complex. Especially for those tumors with transcriptional and thus reversible downregulation of E-cadherin expression, these drug agents offer important therapeutic opportunities.
Handbook of experimental pharmacology 01/2004;
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ABSTRACT: Tumor progression requires the dispersion of epithelial cells from neoplastic clusters and cell invasion of adjacent stromal connective tissue. Aiming at demonstrating the precise relationships between cell dispersion and cell invasion, related respectively to expression of E-cadherin/catenin complex and matrix metalloproteinases (MMPs), we developed an original in vitro model of cell dispersion analysis. Our study reports the validation of this model that allowed us to analyze and quantify the cell cohesion level by means of time-lapse videomicroscopy and computer analysis based on the observation of spatial and temporal cell distribution. Our model was able to distinguish 2 groups among different human bronchial and mammary epithelial cells previously characterized for the expression of E-cadherin/catenin complex and MMPs and their invasive capacity in the Boyden chamber assay. The first group (16HBE14o(-), MCF-7, T47D) that expressed membranous E-cadherin and beta-catenin, and was negative for MMP-2 expression and non-invasive, displayed a highly cohesive pattern corresponding to a cluster spatial distribution. The second group (Beas2B, BZR, BZR-T33, MDA-MB-231, MDA-MB-435, BT549 and HS578T) that was invasive and showed lack of expression of E-cadherin and a cytoplasmic redistribution of beta-catenin, displayed a dispersed pattern corresponding to a random spatial distribution. Downregulation of E-cadherin by a blocking antibody induced a more random distribution. Conversely, expression of E-cadherin by cDNA transfection induced a cluster distribution. Moreover, tumor cell lines that co-expressed MT1-MMP and MMP-2 (Beas2B, BZR, BZR-T33, MDA-MB-435, BT549 and HS578T) showed a more dispersed pattern than tumor cell lines that did not express MMP-2 (MDA-MB-231). In conclusion, we demonstrated that the spatial group behavior of cell lines, i.e., their cohesion/dispersion ability, reflects their invasive properties. Thus, this model of cell dispersion analysis may represent a new test to measure tumor cell aggressiveness.
International Journal of Cancer 10/2001; 93(5):644-52. · 5.44 Impact Factor
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ABSTRACT: The invasion suppressor gene E-CADHERIN (CDH1) is downregulated in a large variety of human carcinomas. Up to now, mutational analysis of the CDH1 gene has been described for 325 tumors derived from only four different tissue types. A simple but sensitive mutation detection assay is needed to screen many more tumor types, possibly bearing E-cadherin inactivating mutations. For that purpose, we developed a multiplex PCR-SSCP analysis for all 16 CDH1 exons. Ease of experimentation was combined with reliable sensitivity. Indeed, the present multiplex analysis reduces the number of manipulations to 50%, while the mutation detection turned out to be highly efficient and sensitive.
Human Mutation 02/1997; 9(6):567-74. · 5.69 Impact Factor
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ABSTRACT: We have analysed a series of 49 human breast cancers for mutations in the entire coding region plus flanking intron sequences of the E-cadherin gene. The tumours included 41 infiltrating lobular carcinomas, two infiltrating ducto-lobular carcinomas and six infiltrative ductal carcinomas. In the lobular carcinomas 23 different somatic mutations were detected, of which seven were insertions, 11 deletions, two nonsense mutations and three splice site mutations. The other tumours showed no detectable E-cadherin mutations. All the frameshift and nonsense mutations are expected to generate a secreted E-cadherin fragment instead of a transmembrane protein with cell adhesion activity. The majority of the mutations (21 of 23) were found in combination with loss of heterozygosity of the wild type E-cadherin locus (16q22.1), a hallmark of classical tumour suppressor genes. The mutations were scattered over the whole coding region and no hot spots could be identified. All mutations described here were previously unreported. In conclusion, we have identified up to now E-cadherin mutations in 27 of 48 (56%) infiltrating lobular breast carcinomas and in 0 of 50 breast cancers of other histopathological subtypes. These data provide strong evidence that frequent E-cadherin mutations are involved in the particular etiology of sporadic lobular breast cancers.
Oncogene 12/1996; 13(9):1919-25. · 6.37 Impact Factor
