The Role of TGF-β/SMAD4 Signaling in Cancer

Int J Biol Sci. 2018 Jan 12;14(2):111-123. doi: 10.7150/ijbs.23230. eCollection 2018.


Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator.

Keywords: SMAD4; TGF-β; mouse model; prognosis; tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DNA Damage / genetics
  • DNA Repair
  • Epithelial-Mesenchymal Transition / genetics
  • Mice
  • Models, Molecular
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Prognosis
  • Signal Transduction
  • Smad4 Protein / genetics*
  • Smad4 Protein / metabolism
  • Smad4 Protein / physiology
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / physiology*


  • Smad4 Protein
  • Smad4 protein, mouse
  • Transforming Growth Factor beta