Insulin-like growth factor binding protein-3 expression is associated with growth stimulation of T47D human breast cancer cells: the role of altered epidermal growth factor signaling

J Clin Endocrinol Metab. 2004 Apr;89(4):1950-6. doi: 10.1210/jc.2003-030914.


IGF binding protein (IGFBP)-3 has antiproliferative and proapoptotic effects on the growth of human breast cancer cells in vitro. However, clinical studies suggest that high levels of IGFBP-3 in breast tumor tissue are associated with large, highly proliferative tumors. In this study, we examined the effects of stable transfection with human IGFBP-3 cDNA on the growth of T47D human breast cancer cells in vitro and in vivo. Expression of IGFBP-3 initially inhibited the growth of T47D in vitro but was associated with enhanced growth in vivo. Furthermore, IGFBP-3-expressing cells in vitro became growth stimulated at higher passages post transfection, suggesting breast cancer cells may switch their response to IGFBP-3 with increasing tumorigenicity. These stimulatory effects observed in IGFBP-3-expressing cells were associated with an enhanced responsiveness to the proliferative effects of epidermal growth factor (EGF). When EGF receptor (EGFR) kinase activity was blocked using PD153035, high passage IGFBP-3 transfectants were growth inhibited compared with controls treated with inhibitor. These findings suggest that the interaction between IGFBP-3 and the EGFR system is central to whether IGFBP-3 acts as a growth stimulator or inhibitor in breast cancer cells and that therapies targeting EGFR may have increased efficacy in breast tumors expressing high levels of IGFBP-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Division
  • Cell Line, Tumor
  • Epidermal Growth Factor / metabolism*
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • Mice
  • Mice, Nude
  • Signal Transduction*
  • Up-Regulation


  • Insulin-Like Growth Factor Binding Protein 3
  • Epidermal Growth Factor
  • ErbB Receptors