PI3-kinase/p38 kinase-dependent E2F1 activation is critical for Pin1 induction in tamoxifen-resistant breast cancer cells

Mol Cells. 2011 Jul;32(1):107-11. doi: 10.1007/s10059-011-0074-y. Epub 2011 May 11.


Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. We have shown that Pin1, a peptidyl prolyl isomerase, is consistently overexpressed in TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) and plays a key role in the enhanced angiogenic potential of TAMR-MCF-7 cells. In the present study, we focused on signaling pathways for Pin1 up-regulation in TAMR-MCF-7 cells. Relative to MCF-7 cells, Pin1 gene transcription and E2 transcription factor1 (E2F1) expression were enhanced in TAMR-MCF-7 cells. E2F1 siRNA significantly reduced both the protein expression and the promoter transcriptional activity of Pin1. Activities of phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and p38 kinase were all higher in TAMR-MCF-7 cells than in control MCF-7 cells and the enhanced Pin1 and E2F1 expression in TAMR-MCF-7 cells was reversed by inhibition of PI3K or p38 kinase. Moreover, the higher production of vascular endothelial growth factor (VEGF) in TAMR-MCF-7 cells was significantly diminished by suppression of PI3K or p38 kinase. These results suggest that Pin1 overexpression and subsequent VEGF production in TAMR-MCF-7 cells are mediated through PI3-kinase or p38 kinase-dependent E2F1 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Blotting, Western
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing / drug effects
  • Genes, Reporter
  • Humans
  • Luciferases / analysis
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Signal Transduction
  • Tamoxifen / pharmacology*
  • Tamoxifen / therapeutic use
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antineoplastic Agents, Hormonal
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • NIMA-Interacting Peptidylprolyl Isomerase
  • RNA, Small Interfering
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Tamoxifen
  • Luciferases
  • Phosphatidylinositol 3-Kinases
  • p38 Mitogen-Activated Protein Kinases
  • PIN1 protein, human
  • Peptidylprolyl Isomerase