Involvement of Pin1 induction in epithelial-mesenchymal transition of tamoxifen-resistant breast cancer cells

Cancer Sci. 2009 Oct;100(10):1834-41. doi: 10.1111/j.1349-7006.2009.01260.x. Epub 2009 Jul 24.


Acquisition of resistance to tamoxifen is a critical therapeutic problem in breast cancer patients. Epithelial-mesenchymal transition (EMT), where cells undergo a developmental switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype, is associated with invasion and motility of cancer cells. Here, we found that tamoxifen-resistant (TAMR)-MCF-7 cells had undergone EMT, as evidenced by mesenchymal-like cell shape, downregulation of basal E-cadherin expression, and overexpression of N-cadherin and vimentin, as well as increased Snail transcriptional activity and protein expression. Given the roles of glycogen synthase kinase (GSK)-3beta and nuclear factor (NF)-kappaB in Snail-mediated E-cadherin deregulation during EMT, we examined the role of these signaling pathways in the EMT of TAMR-MCF-7 cells. Both Ser9-phosphorylated GSK-3beta (inactive form) and NF-kappaB reporter activity were increased in TAMR-MCF-7 cells, as was activation of the phosphatase and tensin homolog depleted on chromosome ten (PTEN)-phosphoinositide 3 (PI3)-kinase-Akt pathway. Pin1, a peptidyl-prolyl isomerase, was overexpressed in TAMR-MCF-7 cells, and Snail transcription and the expression of EMT markers could be decreased by Pin1 siRNA treatment. These results imply that Pin1 overexpression in TAMR-MCF-7 cells is involved in the EMT process via PTEN-PI3-kinase-Akt-GSK-3beta and/or GSK-3beta-NF-kappaB-dependent Snail activation, and suggest the potential involvement of Pin1 in EMT during breast cancer development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / physiology*
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Immunoblotting
  • Mesoderm / pathology
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neoplasm Invasiveness / pathology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering
  • Selective Estrogen Receptor Modulators / pharmacology
  • Signal Transduction / physiology*
  • Snail Family Transcription Factors
  • Tamoxifen / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Cadherins
  • NF-kappa B
  • NIMA-Interacting Peptidylprolyl Isomerase
  • RNA, Small Interfering
  • Selective Estrogen Receptor Modulators
  • Snail Family Transcription Factors
  • Transcription Factors
  • Tamoxifen
  • Phosphatidylinositol 3-Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • PTEN Phosphohydrolase
  • PIN1 protein, human
  • Peptidylprolyl Isomerase