Enhancement of vascular endothelial growth factor-mediated angiogenesis in tamoxifen-resistant breast cancer cells: role of Pin1 overexpression

Mol Cancer Ther. 2009 Aug;8(8):2163-71. doi: 10.1158/1535-7163.MCT-08-1061. Epub 2009 Aug 11.

Abstract

Acquired resistance to tamoxifen (TAM) is a serious therapeutic problem in breast cancer patients. Here, we found that TAM-resistant MCF-7 cells (TAMR-MCF-7 cells) produced higher levels of vascular endothelial growth factor (VEGF) than control MCF-7 cells. Molecular analyses using reporter genes and Western blots supported the involvement of c-Jun/activator protein-1 and hypoxia-inducible factor 1alpha in enhanced VEGF transcription in TAMR-MCF-7 cells. Pin1, a peptidyl prolyl isomerase, was consistently overexpressed in TAMR-MCF-7 cells, and c-Jun/activator protein-1-dependent VEGF transcription in TAMR-MCF-7 cells was almost completely inhibited by Pin1 siRNA and by the Pin1 inhibitor juglone. Chick chorioallantoic membrane assays confirmed that the increased angiogenic intensity of TAMR-MCF-7 cells was significantly suppressed by Pin1 inhibition. These results show that Pin1 overexpression is closely associated with VEGF-mediated angiogenesis and suggest that Pin1 is a potential therapeutic target of excessive angiogenesis in TAM-resistant breast cancer cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Peptidylprolyl Isomerase / genetics*
  • Peptidylprolyl Isomerase / metabolism
  • Tamoxifen / pharmacology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Antineoplastic Agents, Hormonal
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Transcription Factor AP-1
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Tamoxifen
  • PIN1 protein, human
  • Peptidylprolyl Isomerase