SMAD4 and colorectal cancer: Dysregulation of TGF-β signaling is often observed during cancer initiation and progression.1–3 Genetic inactivation of TβRII occurs in approximately 25% of colorectal cancer.15 Smad4, the central component of TGF-β signaling, has frequently been deleted in sporadic colorectal cancer and pancreatic cancer.16 However, the TGF-β pathway remains relatively intact in most cancer types, possibly because cancer cells benefit from signaling for subsequent malignancy.