Mysteries of TGF-β paradox in benign and malignant cells

Qiang Zhang, Nengwang Yu, Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-β paradox. To date, the mechanism of this paradox still remains a scientific mystery. In this review, we present our experience, along with the literature, in an attempt to answer this mystery. First, we observed that, on TGF-β engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies.

Original languageEnglish (US)
Article number94
JournalFrontiers in Oncology
Volume4 MAY
StatePublished - 2014


  • Erk activation
  • PP2A recruitment
  • Positive feedback
  • Smad activation
  • TGF-β auto-induction
  • TGF-β paradox
  • TGF-β receptors
  • negative feedback

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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