Antiproliferative actions of insulin-like growth factor binding protein (IGFBP)-3 in human breast cancer cells

Youngman Oh, Zoran Gucev, Lilly Ng, Hermann L. Müller, Ronald (Ron) Rosenfeld

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

A number of lines of evidence suggest that IGFs are important mitogens in human breast cancer: (1) IGFs are the most potent growth factor in human breast cancer cells; (2) estrogen stimulates expression of IGF-II and the type 1 IGF receptor; and (3) stromal cells express IGFs, which may act in a paracrine manner. Numerous studies have demonstrated that IGFBPs modulate the mitogenic effects of IGFs in the local environment. In particular, we have recently demonstrated that IGFBP-3 inhibits the growth of Hs578T and MDA-MB-231 human breast cancer cells in an IGF-independent manner. Further studies revealed the existence of cell surface-associated IGFBP-3 receptors. Receptor binding and the subsequent antiproliferative action of IGFBP-3 was inhibited by IGFs, owing to the formation of an IGF-IGFBP-3 complex that prevents the binding of IGFBP-3 to its receptors. In addition, exogeneously added soluble heparin or heparan sulfate inhibited the binding of IGFBP-3 to the cell surface in a dose-dependent manner. However, when heparin and heparan sulfate linkages of glycosaminoglycans on the cell surface were enzymatically removed, IGFBP-3 binding was only minimally affected. These data suggest that soluble heparin or heparan sulfate forms a complex with IGFBP-3, thereby inhibiting receptor binding of IGFBP-3, rather than competing with cell-surface glycosaminoglycans for binding of IGFBP-3. Additionally, the role of IGFBP-3 in the antiproliferative effects of transforming growth factor (TGF)-β and retinoic acid (RA) is supported by out observations that: (1) inhibition of IGFBP-3 gene expression using an IGFBP-3 antisense oligodeoxynucleotide not only blocks TGF-β and RA simulation of IGFBP-3 production by up to 90%, but also inhibits their antiproliferative effects by 40-60%; and (2) treatment with IGF-II and IGF-II analogs diminish TGF-β effects by blocking TGF-β induced binding of IGFBP-3 to the cell surface. Taken together, our results support the hypothesis that IGFBP-3 is an important antiproliferative factor in human breast cancer, acting in an IGF-independent manner in addition to its ability to modulate the binding of IGF peptides to IGF receptors.

Original languageEnglish (US)
Pages (from-to)503-512
Number of pages10
JournalProgress in Growth Factor Research
Volume6
Issue number2-4
DOIs
StatePublished - 1995

Fingerprint

Insulin-Like Growth Factor Binding Protein 3
Cells
Breast Neoplasms
Transforming Growth Factors
Insulin-Like Growth Factor II
Heparitin Sulfate
Heparin
human IGFBP3 protein
Tretinoin
Glycosaminoglycans
Insulin-Like Growth Factor I
Insulin-Like Growth Factor Binding Proteins
IGF Type 1 Receptor
Oligodeoxyribonucleotides
Stromal Cells
Mitogens

Keywords

  • antiproliferation
  • breast cancer
  • glycosaminoglycan
  • IGFBP-3
  • IGFBP-3 receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology
  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy

Cite this

Antiproliferative actions of insulin-like growth factor binding protein (IGFBP)-3 in human breast cancer cells. / Oh, Youngman; Gucev, Zoran; Ng, Lilly; Müller, Hermann L.; Rosenfeld, Ronald (Ron).

In: Progress in Growth Factor Research, Vol. 6, No. 2-4, 1995, p. 503-512.

Research output: Contribution to journalArticle

Oh, Youngman ; Gucev, Zoran ; Ng, Lilly ; Müller, Hermann L. ; Rosenfeld, Ronald (Ron). / Antiproliferative actions of insulin-like growth factor binding protein (IGFBP)-3 in human breast cancer cells. In: Progress in Growth Factor Research. 1995 ; Vol. 6, No. 2-4. pp. 503-512.
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