**2.5 Role of p130Cas in TGF-beta signalling in breast cancer cells**

Transforming growth factor-beta (TGF-beta) is a powerful suppressor of mammary tumorigenesis because of its ability to repress mammary epithelial cell proliferation, as well as through its creation of cell microenvironments that inhibit mammary epithelial cells (MECs) motility, invasion, and metastasis. Yet, paradoxically, cancer cells elicit mechanisms that subvert the tumour suppressing functions of TGF-beta, and in doing so, confer oncogenic and metastatic activities upon this multifunctional cytokine (Massague, 2008). In epithelial cells, integrin beta1 suppresses apoptosis and growth inhibition induced by TGFbeta (Zhang *et al.*, 2003). In this context p130Cas has been shown to be a crucial player by binding to Smad3, and preventing its phosphorylation by TGF-beta receptor. As a consequence, the transcription of the cyclin-dependent kinase inhibitors p15 and p21 is inhibited, resulting in cell cycle progression (Kim *et al.*, 2008). Recently, it has been reported that p130Cas over-expression in MECs shifts TGF-beta signalling from Smad2/SMAD3 phosphorylation to p38 MAPK activation, rendering MECs resistant to TGF-beta -induced growth arrest and enhancing their metastatic potential (Wendt *et al.*, 2009). Overall, p130Cas can act as a molecular rheostat that switches the tumour suppressor function of TGF-beta to a pro-metastatic role during breast cancer progression.
