OVOL2 antagonizes TGF-β signaling to regulate epithelial to mesenchymal transition during mammary tumor metastasis

Oncotarget. 2017 Jun 13;8(24):39401-39416. doi: 10.18632/oncotarget.17031.


Great progress has been achieved in the study of the role of TGF-β signaling in triggering epithelial-mesenchymal transition (EMT) in a variety of cancers; however, the regulation of TGF-β signaling during EMT in mammary tumor metastasis has not been completely defined. In the present study, we demonstrated that OVOL2, a zinc finger transcription factor, inhibits TGF-β signaling-induced EMT in mouse and human mammary tumor cells, as well as in mouse tumor models. Data from the Oncomine databases indicated a strong negative relationship between OVOL2 expression and breast cancer progression. Moreover, our experiments revealed that OVOL2 inhibits TGF-β signaling at multiple levels, including inhibiting Smad4 mRNA expression and inducing Smad7 mRNA expression, blocking the binding between Smad4 and target DNA, and interfering with complex formation between Smad4 and Smad2/3. These findings reveal a novel mechanism that controls the TGF-β signaling output level in vitro and in vivo. The modulation of these molecular processes may represent a strategy for inhibiting breast cancer invasion by restoring OVOL2 expression.

Keywords: EMT; OVOL2; Smad4; TGF-β signaling; mammary tumor.

MeSH terms

  • Animals
  • Biomarkers
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition* / genetics
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • Neoplasm Metastasis
  • Prognosis
  • Protein Binding
  • Signal Transduction*
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • Biomarkers
  • DNA-Binding Proteins
  • Ovol2 protein, human
  • SMAD4 protein, human
  • SMAD7 protein, human
  • Smad4 Protein
  • Smad7 Protein
  • Transcription Factors
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins