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Endocrinology Vol. 140, No. 3 1319-1328
Copyright © 1999 by The Endocrine Society

ARTICLES

Characterization of Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) Binding to Human Breast Cancer Cells: Kinetics of IGFBP-3 Binding and Identification of Receptor Binding Domain on the IGFBP-3 Molecule1

Yoshitaka Yamanaka, John L. Fowlkes, Elizabeth M. Wilson, Ron G. Rosenfeld and Youngman Oh

Department of Pediatrics (Y.Y., E.M.W., R.G.R., Y.O.), School of Medicine, Oregon Health Sciences University, Portland, Oregon 97201; and Department of Pediatrics (J.L.F.), University of Kentucky, Lexington, Kentucky 40536

Address all correspondence and requests for reprints to: Youngman Oh, Department of Pediatrics, NRC 5, School of Medicine, Oregon Health Sciences University, Portland, Oregon 97201-3042.

Insulin-like growth factor binding protein-3 (IGFBP-3) binds to specific membrane proteins located on human breast cancer cells, which may be responsible for mediating the IGF-independent growth inhibitory effects of IGFBP-3. In this study, we evaluated IGFBP-3 binding sites on breast cancer cell membranes by competitive binding studies with IGFBP-1 through -6 and various forms of IGFBP-3, including synthetic IGFBP-3 fragments. Scatchard analysis revealed the existence of high-affinity sites for IGFBP-3 in estrogen receptor-negative Hs578T human breast cancer cells (dissociation constant (Kd) = 8.19 ± 0.97 x 10-9 M and 4.92 ± 1.51 x 105 binding sites/cell) and 30-fold fewer receptors in estrogen receptor-positive MCF-7 cells (Kd = 8.49 ± 0.78 x 10-9 M and 1.72 ± 0.31 x 104 binding sites/cell), using a one-site model. These data demonstrate binding characteristics of typical receptor-ligand interactions, strongly suggesting an IGFBP-3:IGFBP-3 receptor interaction. Among IGFBPs, only IGFBP-5 showed weak competition, indicating that IGFBP-3 binding to breast cancer cell surfaces is specific and cannot be attributed to nonspecific interaction with glycosaminoglycans. This was confirmed by showing that synthetic IGFBP-3 peptides containing IGFBP-3 glycosaminoglycan-binding domains competed only weakly for IGFBP-3 binding to the cell surface. Rat IGFBP-3 was 20-fold less potent in its ability to compete with human IGFBP-3Escherichia coli, as well as 10- to 20-fold less potent for cell growth inhibition than human IGFBP-3, suggesting the existence of species specificity in the interaction between IGFBP-3 and the IGFBP-3 receptor. When various IGFBP-3 fragments were evaluated for affinity for the IGFBP-3 receptor, only those fragments that contain the midregion of the IGFBP-3 molecule were able to inhibit 125I-IGFBP-3Escherichia coli binding, indicating that the midregion of the IGFBP-3 molecule is responsible for binding to its receptor. These observations demonstrate that specific, high-affinity IGFBP-3 receptors are located on breast cancer cell membranes. These receptors have properties that support the notion that they may mediate the IGF-independent inhibitory actions of IGFBP-3 in breast cancer cells.




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