Recombinant insulin‐like growth factor binding protein‐1 inhibits IGF‐I, serum, and estrogen‐dependent growth of MCF‐7 human breast cancer cells

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Abstract
The insulin‐like growth factors (IGFs) are potent mitogens for breast cancer cells and their activity is modulated by high affinity binding proteins (IGFBPs). We have recently shown that IGFBP‐1 purified from human amniotic fluid neutralizes IGF‐I‐dependent growth of MCF‐7 cells. In this study we examined the effects of recombinant IGFBP‐1 (rBP‐1) on IGF‐I, estradiol (E2), and serum‐induced monolayer and anchorage independent growth (AIG) of MCF‐7 cells. Under serum‐free conditions, rBP‐1 had no effect on MCF‐7 basal monolayer growth. However, 40 nM rBP‐1 completely blocked the mitogenic action of both IGF‐I and 5% charcoal stripped serum (CSS). This concentration of rBP‐1 partially inhibited E2‐induced growth, while 80 nM rBP‐1 completely abolished E2 mitogenicity. The addition of either excess IGF‐I or 5 nM [Arg3]IGF‐I, a species that does not bind IGFBPs, neutralized rBP‐1 inhibitory effects. In AIG assays, 80 nM rBP‐1 reduced colony number by at least 70% and decreased colony size in all treatment groups compared to control. We examined rBP‐1 effects on both IGF‐I binding to MCF‐7 membranes and activation of type I IGF receptor (IGFR1) and found that 80 nM rBP‐1 reduced IGF‐I receptor binding to levels of nonspecific binding and completely abolished ligand‐dependent IGFR, phosphorylation. However, neither treatment with 5% CSS nor exposure to E2 resulted in IGFR1 phosphorylation suggesting that different mechanism(s) are responsible for rBP‐1 inhibitory action under this condition. Our data suggest rBP‐1 may serve as an antagonist of human breast cancer growth by interfering with growth factor‐mediated cell proliferation.

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