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Insulin-like growth factor binding protein 3 has opposing actions on malignant and nonmalignant breast epithelial

C Burrows1, J M P Holly, N J Laurence

  • 1Department of Clinical Sciences at North Bristol, IGFs and Metabolic Endocrinology Group, University of Bristol, The Medical School, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom.

Endocrinology
|April 15, 2006
PubMed

Insights

Insulin-like growth factor-binding protein 3 (IGFBP-3) exhibits dual actions on breast epithelial cells. Its effects on cell growth and survival depend on cholesterol-stabilized integrin receptor complexes and fibronectin presence.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Insulin-like growth factor-binding protein 3 (IGFBP-3) is typically viewed as counteracting IGF actions and is explored for cancer therapy.
  • However, elevated IGFBP-3 levels in breast tumors correlate with aggressive disease and poor prognosis.
  • This suggests context-dependent roles for IGFBP-3 in breast cancer progression.

Purpose of the Study:

  • To investigate the factors determining whether IGFBP-3 exerts positive or negative effects on breast epithelial cells.
  • To elucidate the mechanisms underlying IGFBP-3's differential actions in various cellular contexts.

Main Methods:

  • Utilized three breast epithelial cell lines (Hs578T, MCF-7, MCF-10A) cultured on different extracellular matrix components (collagen, laminin, fibronectin).
  • Assessed cell attachment, apoptosis, growth, and survival under various conditions, including treatment with IGFBP-3, a serine phosphorylation domain peptide, IGF-I, MAPK inhibitors, and beta1-integrin antibodies.
  • Investigated molecular interactions of IGFBP-3 with caveolin-1, beta1-integrins, focal adhesion kinase, and MAPK signaling pathways.

Main Results:

  • IGFBP-3 promoted attachment and survival of Hs578T cells on fibronectin, contrasting its effects on collagen/laminin.
  • IGFBP-3's pro-survival effects on Hs578T and MCF-7 cells were linked to beta1-integrin, MAPK signaling, and cholesterol-stabilized complexes.
  • IGFBP-3 promoted growth and survival in nonmalignant MCF-10A cells, but these effects were context-dependent, being reversed by fibronectin, beta1-integrin blockade, or disruption of cholesterol-stabilized complexes.
  • On Hs578T cells, IGFBP-3 bound to caveolin-1 and beta1-integrins, promoting aggregation and activating MAPK signaling.

Conclusions:

  • IGFBP-3 exhibits context-dependent actions on breast epithelial cells, influencing growth and survival.
  • The status of cholesterol-stabilized integrin receptor complexes and the extracellular matrix component fibronectin are critical determinants of IGFBP-3's effects.
  • These findings highlight the complex role of IGFBP-3 in breast cancer and suggest therapeutic strategies targeting these molecular interactions.

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