| Abstract: | The insulin-like growth factors (IGFs) are potent mitogens for malignant cell proliferation. The majority of secreted IGFs are bound to specific IGF-binding proteins (IGFBPs) that are secreted by a large number of cells. These proteins may either inhibit or enhance IGF actions. Breast carcinoma cells secrete a variety of IGFBPs. We have previously demonstrated that retinoic acid (RA) inhibition of IGF-l– stimulated MCF-7 cell proliferation is associated with increased IGFBP-3 levels in the conditioned media. We therefore investigated the effect of recombinant IGFBP-3 as well as IGFBP-2, -4 and -5 on IGF-l stimulation of DNA synthesis and IGF-I binding in the MCF-7 human breast carcinoma cell line. IGFBP-2 and -3 enhanced IGF-l stimulation of DNA synthesis in MCF-7 cells while IGFBP-4 and -5 had no effect. Transfection of MCF-7 cells with an IGFBP-3 expression vector resulted in the enhanced secretion of IGFBP-3 with an accompanying increase in IGF-l binding as well as increased cell proliferation upon treatment of the cells with IGF-l. IGF-l preincubation of MCF-7 cells transfected with control pSVneo plasmids results in cells refractory to further IGF-l stimulation of thymidine incorporation while IGF-l continues to stimulate 3H]-thymidine incorporation in IGFBP-3–transfected MCF-7 cells, suggesting that IGFBP-3 protects the cells from IGF-l–mediated down regulation of its receptor. Therefore, IGFBP-3 secreted by MCF-7 cells can enhance IGF-l stimulation of DNA synthesis, increase IGF-l binding to these cells, and prevent IGF-l–induced desensitization of its own receptor, suggesting that IGFBP-3 plays a significant role in IGF-l–mediated breast carcinoma proliferation. © 1994 Wiley-Liss, Inc. |
