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 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.