SMAD4 and neoplasm: Mutation of K-Ras acts as an initiating event in development of PADC; whereas, alterations of Smad4 occur during progression of the disease [4,5] [6].  Smad4 is necessary for canonical TGF-β /Smad signaling and mutation of Smad4 is a major mechanism causing loss of TGF-β tumor suppressor activity.