Inhibition of insulin-like growth factor I receptor signaling by the vitamin D analogue EB1089 in MCF-7 breast cancer cells: A role for insulin-like growth factor binding proteins.

Insulin-like growth factors I and II (IGF-I and IGF-II) are potent mitogens involved in growth regulation of breast epithelial cells and are implicated in the pathophysiology of breast cancer. Their bioactivity is enhanced or inhibited by specific IGF-binding proteins (IGFBPs). Vitamin D-related compounds (VDRCs) have been shown to inhibit proliferation and induce apoptosis of MCF-7 breast carcinoma cells. We have previously demonstrated that VDRCs antagonize the growth-promoting activity of IGF-I by stimulating autocrine production of IGFBP-5 in MCF-7 cells, but the effect of VDRCs on IGF-I receptor (IGF-IR) intracellular signaling has not been elucidated. We report here that the vitamin D analogue EB1089 interferes with the IGF-IR signaling pathway by attenuating IGF-I-induced tyrosine phosphorylation of IRS-1, and to a lesser extent, IRS-2. It does not affect protein levels of IRS-1, IRS-2 or IGF-IR. However, EB1089 does not inhibit tyrosine phosphorylation of IRS-1 induced by des(1-3) IGF-I, an IGF-I analogue with greatly reduced affinity for IGFBPs. Furthermore, we demonstrate that an antisense IGFBP-5 oligodeoxynucleotide attenuates EB1089-induced inhibition of IGF-I-stimulated tyrosine phosphorylation of IRS-1 and EB1089-induced IGFBP-5 accumulation. These data strongly suggest that IGFBP-5 plays a functional role in the interfering action of EB1089 with the IGF-IR signal transduction pathway.