SMAD4 and cancer: SMAD4 expression is altered with the loss of its tumor suppressive effect, TGFβ pathway is dysfunctional (TGF-β → SMAD2/3 → SMAD4 altered) in EAC, compared to the normal esophagus and BE, with the function of SMADs often being lost absent in EACs (SMAD2, -4 are mostly affected), a phenomenon that can promote EMT, cancer cell invasion, and metastasis in BE [134,135,136].