SMAD4 and neoplasm: Given the distinct pattern of these gene expression changes, we investigated whether inactivation of Smad4 could facilitate tumorigenesis driven by Braf and Myc. Indeed, loss of Smad4 rendered wild-type mice more susceptible to BRAF-driven tumorigenesis, while combined expression of activated Braf and Myc in the background of Smad4 knockout nearly completely compensated for KRAS loss in promoting tumor survival and growth (Fig. 7c, d).