Antiproliferative action of tumor necrosis factor-alpha on MCF-7 breastcancer cells is associated with increased insulin-like growth factor binding protein-3 accumulation.
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.
Rozen
F
F
Lady Davis Research Institute of the Jewish General Hospital and Departments of Medicine and Oncology, McGill University, Montreal, Quebec, H3T 1E2, Canada.
Zhang
J
J
Pollak
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D004958:Estradiol; D013936:Thymidine