Insulin-like growth factor-binding protein-5 inhibits the growth of human breast cancer cells in vitro and in vivo

J Biol Chem. 2003 Aug 8;278(32):29676-85. doi: 10.1074/jbc.M301965200. Epub 2003 May 30.


The role of insulin-like growth factor-binding protein (IGFBP)-5 in human breast cancer cell growth is unclear. We determined the effects of IGFBP-5 expression on the growth of human breast cancer cell lines in vivo and in vitro. Expression of IGFBP-5, both by stable transfection and adenoviral-mediated infection, was inhibitory to the growth of MDA-MB-231 and Hs578T human breast cancer cells over a 13-day period. IGFBP-5 expression resulted in a G2/M cell cycle arrest and the induction of apoptosis in both cell lines, an effect that was abrogated in the presence of the broad-spectrum caspase inhibitor, z-VAD-fmk. IGFBP-5-induced apoptosis was associated with a transcriptional increase in expression of the proapoptotic regulator bax and decrease in the anti-apoptotic bcl-2 compared with vector controls. Secreted IGFBP-5 when added exogenously to breast cancer cells was not internalized and had no effect on cell growth or apoptosis, suggesting that IGFBP-5 may elicit its inhibitory effects via a novel, intracrine mechanism. In athymic nude mice, stable expression of IGFBP-5 significantly inhibited both the formation and growth of tumors derived from MDA-MB-231 cells. IGFBP-5-expressing tumors also had a significantly elevated level of bax mRNA and decreased levels of bcl-2 mRNA compared with vector tumors. These data suggest that IGFBP-5 is a potent growth inhibitor and proapoptotic agent in human breast cancer cells via modulation of cell cycle regulation and apoptotic mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis
  • Blotting, Northern
  • Breast Neoplasms / metabolism*
  • Cell Cycle
  • Cell Division
  • Culture Media, Conditioned / pharmacology
  • DNA Fragmentation
  • Dose-Response Relationship, Radiation
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • Genetic Vectors
  • Humans
  • Immunoblotting
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism
  • Insulin-Like Growth Factor Binding Protein 5 / physiology*
  • Ligands
  • Mice
  • Mice, Nude
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Thymidine / pharmacology
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • bcl-2-Associated X Protein


  • Amino Acid Chloromethyl Ketones
  • BAX protein, human
  • Bax protein, mouse
  • Culture Media, Conditioned
  • Enzyme Inhibitors
  • Insulin-Like Growth Factor Binding Protein 5
  • Ligands
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • bcl-2-Associated X Protein
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Thymidine