SMAD2 and cancer: However, resistance to TGF-β in cancer may occur through several mechanisms such as reduced expression of TβRI and/or TβRII, mutations or functional inactivation of TβRII, inactivating mutations in Smad2 and Smad4 and overexpression of inhibitory proteins including Smad7 (Kleeff et al, 1999; Halder et al, 2005).