Additionally, we found that the presence of P-cadherin is able to provoke the secretion of pro-invasive factors, such as matrix metalloproteases (MMPs), MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. In this study, we show for the first time that P-cadherin overexpression, in wild-type E-cadherin breast cancer cells, is able to induce increased cell invasion, motility and migration. Indeed, it is possible to see that there is a significant association between P-cadherin overexpression and the invasion capacity of breast cancer cells that maintain the expression of wild-type E-cadherin. Thus, we have studied earlier the expression of classical cadherins in a small collection of breast cancer cell lines ( Paredes et al., 2007), and we associated this expression with the invasiveness potential of these cells. On the basis of these observations, we aimed to understand how P-cadherin, in an E-cadherin wild-type background, could influence the behaviour of these tumours. In clinical terms, these P-cadherin-overexpressing tumours present high histological grade, with decreased cell polarity, aggressive behaviour and worse patient survival ( Peralta Soler et al., 1999 Gamallo et al., 2001 Paredes et al., 2002, 2005). In contrast, these tumours overexpress P-cadherin, maintaining the normal E-cadherin expression ( Paredes et al., 2005, 2008). As mentioned before, in breast cancer, many of the highly aggressive tumours do not actually show a cadherin switch. Our group has been focused in studying the role of another classical cadherin in breast cancer, namely P-cadherin. For instance, the majority of breast cancer subtypes are diagnosed as invasive and malignant under pathological criteria, but rarely loose complete E-cadherin expression and infrequently gain de novo N-cadherin expression ( Sarrio et al., 2008). However, regardless the major progress in understanding the in vitro molecular processes underlying EMT and tumour progression, a number of questions remain unsolved. This cadherin switch leads to the inhibition of cellвЂ“cell contacts and elicits active signals, which support tumour cell migration, invasion and metastatic dissemination ( Frixen et al., 1991 Chen et al., 1997). During EMT, tumour cells progressively downregulate their cellвЂ“cell adhesion epithelial-specific proteins, such as E-cadherin, and express de novo mesenchymal adhesion molecules, such as N-cadherin. These includes alterations in cellвЂ“cell and cellвЂ“matrix adhesion, activation of small GTPases or modulation of receptor tyrosine kinase-mediated signal transduction pathways ( Cavallaro and Christofori, 2004).Д¬ellвЂ“cell adhesion is crucial for the maintenance of normal epithelial cellular architecture and is frequently altered in tumour progression, inducing a multistep process termed epithelial-to-mesenchymal transition (EMT) ( Thiery, 2002). Recently, a number of molecular mechanisms have been identified in transformed cells that become migratory and invasive during carcinogenesis. Overall, our results contribute to elucidate the mechanism underlying the invasive behaviour of P-cadherin expressing breast tumours.Д¬ell migration and invasion are critical properties that characterize malignant neoplastic cells. Further, we showed that soluble P-cadherin fragment is able to induce in vitro invasion of breast cancer cells.

Moreover, we found that the overexpression of P-cadherin induces the secretion of matrix metalloproteases, specifically MMP-1 and MMP-2, which then lead to P-cadherin ectodomain cleavage. We show that P-cadherin overexpression, in breast cancer cells with wild-type E-cadherin, promotes cell invasion, motility and migration. To achieve this goal, we set up two breast cancer cell models, where P-cadherin expression was differently modulated and analysed in terms of cell invasion, motility and migration. However, little is known about how this protein dictates the very aggressive behaviour of these tumours. In breast cancer, tumours that overexpress P-cadherin usually present a high histological grade, show decreased cell polarity and are associated with worse patient survival. However, during tumour progression, these molecules are frequently altered. Several studies have shown the role mediated by cadherins in this process, besides their role in the maintenance of cell polarity, differentiation and cell growth. CellвЂ“cell adhesion is an elementary process in normal epithelial cellular architecture.

Pcad 2001 viewer