Role of extracellular signal-regulated kinase pathway in RRR-alpha-tocopheryl succinate-induced differentiation of human MDA-MB-435 breast cancer cells

Mol Carcinog. 2002 Apr;33(4):228-36. doi: 10.1002/mc.10040.


RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) induces differentiation of human breast cancer cells. Previous studies ruled out transforming growth factor-beta and c-jun N-terminal kinase involvement in VES-induced differentiation but implicated extracellular signal-regulated kinases (ERKs). Here we show that dominant-negative mutants of either mitogen-activated protein kinase kinase (MEK) 1 or ERK1 blocked VES-induced differentiation of MDA-MB-435 cells, as measured by induction of cytokeratin 18 and p21 (Waf1/Cip1) proteins. Blockage of c-jun protein expression using c-jun antisense oligonucleotides or expression of an inducible dominant-negative c-jun mutant protein inhibited VES-induced differentiation. Elevated expression of wild-type c-jun alone was sufficient to induce cellular differentiation. A role for p21 (Waf1/Cip1) is implicated, in that p21 antisense oligomers blocked VES-induced differentiation. In summary, MEK1, ERK1, the transcription factor c-jun, and the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1) play a part in VES-induced differentiation of human MDA-MB-435 breast cancer cells.

Publication types

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

MeSH terms

  • Breast Neoplasms / pathology*
  • Cell Differentiation / drug effects*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / genetics
  • Doxycycline / pharmacology*
  • Female
  • Genes, jun
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Keratins / genetics
  • MAP Kinase Kinase 1
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinases / genetics*
  • Mitogen-Activated Protein Kinases / metabolism
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • Recombinant Proteins / metabolism
  • Tocopherols
  • Transfection
  • Tumor Cells, Cultured
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology*


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Oligodeoxyribonucleotides, Antisense
  • Proto-Oncogene Proteins c-jun
  • Recombinant Proteins
  • Vitamin E
  • Keratins
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • Doxycycline
  • Tocopherols