Antiproliferative action of tumor necrosis factor-alpha on MCF-7 breastcancer cells is associated with increased insulin-like growth factor binding protein-3 accumulation

Int J Oncol. 1998 Oct;13(4):865-9. doi: 10.3892/ijo.13.4.865.


Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine involved in host response to neoplasia. TNF-alpha has been shown to inhibit proliferation and induce apoptosis of MCF-7 breast carcinoma cells. Insulin-like growth factors I and II (IGF-I and IGF-II) are potent mitogens involved in growth regulation of breast epithelial cells and are implicated in the pathophysiology of breast cancer. Their bioactivity is strongly influenced by specific IGF-binding proteins (IGFBPs). We report that accumulation of IGFBP-3 in the conditioned media of MCF-7 cells is increased over control values in the presence of TNF-alpha. The increased IGFBP-3 accumulation induced by TNF-alpha is correlated with increased IGFBP-3 mRNA abundance. TNF-alpha also decreases IGF-I receptor levels in MCF-7 cells. Estradiol-stimulated MCF-7 cell proliferation is associated with reduced IGFBP-3 accumulation, and we show that TNF-alpha attenuation of estradiol-stimulated proliferation is associated with increased IGFBP-3 accumulation. Finally, we demonstrate that an IGFBP-3 antisense oligodeoxynucleotide antagonizes TNF-alpha-induced inhibition of cell proliferation and TNF-alpha-induced IGFBP-3 accumulation. These data strongly suggest that IGFBP-3 plays a role in modulation of breast cancer cell proliferation by TNF-alpha.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Northern
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Division / drug effects
  • Dose-Response Relationship, Drug
  • Estradiol / pharmacology
  • Gene Expression / drug effects
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / drug effects*
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Thymidine / metabolism
  • Tritium
  • Tumor Cells, Cultured / cytology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Antineoplastic Agents
  • Insulin-Like Growth Factor Binding Protein 3
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Tritium
  • Estradiol
  • Thymidine