In view of the complexity of the interacting pathways that can alter TGF-β1-Smad4 induced phenotypic effects, especially in immortalised human cancer cell lines, we sought to better define the contextual impact of Smad4 LOF to specifically evaluate the Smad4 and TGF-β1 ligand dependency on gene expression in murine models and to translate these findings with respect to human intestinal cancer. This evidence concerns the gene SMAD4 and cancer.