Smad4 acts as a barrier to tumor progression because it lies at a signaling crossroads integrating the TGF-β, Ras/Erk, and Wnt signaling pathways.32 TGF-β has potent antiproliferative activity through the activation of CDK inhibitors such as p14Ink4b and p21WAF1. This evidence concerns the gene SMAD4 and neoplasm.