A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780.

Insulin-like growth factors (IGFs) are potent mitogens for breast cancer cells. Although IGF-binding proteins (IGFBPs) are known to regulate access of IGFs to IGF receptors, their precise biological actions are poorly defined. We observed that the potent antiestrogen ICI 182780 (ICI) increased IGFBP-5 mRNA by 2-3-fold in 9,10-dimethyl-1,2-benzanthracene-induced mammary tumors in vivo. In vitro studies showed that growth inhibition of MCF-7 human breast cancer cells induced by ICI was associated with increased transcription of the IGFBP-5 gene, increased IGFBP-5 mRNA abundance, and increased IGFBP-5 protein accumulation in the conditioned medium. Growth stimulation following estradiol exposure was associated with opposite effects. An IGFBP-5 antisense oligodeoxynucleotide significantly decreased IGFBP-5 accumulation in conditioned media and enhanced MCF-7 cell DNA synthesis. Furthermore, this antisense oligodeoxynucleotide attenuated both antiestrogen-induced IGFBP-5 accumulation and antiestrogen-induced growth inhibition. These data demonstrate that estradiol down-regulates and ICI up-regulates an autocrine IGFBP-5 growth inhibitory pathway in MCF-7 cells and suggest that IGFBP-5 plays a role in modulation of proliferation of breast cancers by estrogens and antiestrogens.