INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN ENHANCEMENT OF INSULIN-LIKE GROWTH FACTOR-I (IGF-I)-MEDIATED DNA-SYNTHESIS AND IGF-I BINDING IN A HUMAN BREAST-CARCINOMA CELL-LINE

The insulin-like growth factors (IGFs) are potent milogens for maligna nt cell proliferation. The majority of secreted IGFs are bound to spec ific IGF-binding proteins (IGFBPs) that are secreted by a large number of cells. These proteins may either inhibit or enhance IGF actions. B reast carcinoma cells secrete a variety of IGFBPs. We have previously demonstrated that retinoic acid (RA) inhibition of IGF-1-stimulated MC F-7 cell proliferation is associated with increased IGFBP-3 levels in the conditioned media. We therefore investigated the effect of recombi nant IGFBP-3 as well as IGFBP-2, -4 and -5 on IGF-I stimulation of DNA synthesis and IGF-I binding in the MCF-7 human breast carcinoma cell line. IGFBP-2 and -3 enhanced IGF-I stimulation of DNA synthesis in MC F-7 cells while IGFBP-4 and -5 had no effect. Transfection of MCF-7 ce lls with an IGFBP-3 expression vector resulted in the enhanced secreti on of IGFBP-3 with an accompanying increase in IGF-I binding as well a s increased cell proliferation upon treatment of the cells with IGF-I. IGF-I preincubation of MCF-7 cells transfected with control pSVneo pl asmids results in cells refractory to further IGF-I stimulation of thy midine incorporation while IGF-I continues to stimulate [H-3]-thymidin e incorporation in IGFBP-3-transfected MCF-7 cells, suggesting that IG FBP-3 protects the cells from IGF-1-mediated down regulation of its re ceptor. Therefore, IGFBP-3 secreted by MCF-7 cells can enhance IGF-I s timulation of DNA synthesis, increase IGF-I binding to these cells, an d prevent IGF-I-induced desensitization of its own receptor, suggestin g that IGFBP-3 plays a significant role in IGF-I-mediated breast carci noma proliferation. (C) 1994 Wiley-Liss, Inc.