Inhibition of insulin-like growth factor signaling pathways in mammary gland by pure antiestrogen ICI 182,780.

Abstract

The antiestrogens ICI 182,780 (ICI) and tamoxifen are clinically useful in the treatment of estrogen receptor-positive breast tumors. We assessed the in vivo effects of ICI, tamoxifen, and estradiol on the insulin-like growth factor (IGF) signaling pathway in the rat mammary gland. ICI significantly decreased the size of the lobular structures, Ki-67 labeling index, and insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-5 gene expression. Treatment of rats with 1, 1.5, and 2 mg of ICI/kg body weight/week resulted in a 2-, 7-, and 8-fold increase in IGFBP-3 transcripts. High doses of ICI increased mammary IGF-1 gene expression by 2-fold (P < 0.01) but decreased IGF-1R and its autophosphorylation to approximately 30% of the control mammary gland. IRS-1, IRS-2, and c-Raf-1 levels in the ICI-treated mammary glands were approximately 30, 15, and 40% of controls, respectively. Basal phosphorylation of IRS-1, Akt-1, and the p85 subunit of phosphatidylinositol 3-kinase (PI-3K) were low but detectable after ICI treatment. Despite a significant reduction in levels of IGF-1R, IRS-1, and IRS-2 phosphorylation, phospho p42/p44 MAPK levels were only slightly decreased. Tamoxifen-induced growth inhibition was associated with slight stimulation of IGFBP-3 gene expression and reduction in IRS-2 levels. Basal phosphorylation of IGF-1R, IRS-1, and p85 subunit of PI-3K was decreased by tamoxifen. Estradiol-induced epithelial cell proliferation was associated with inhibition of IGFBP-3 gene expression, stimulation of IGFBP-2 gene expression, and increases in IGF-1R, IRS-1, IRS-2, and c-Raf-1 levels. Although basal phosphorylation of IGF-1R, IRS-1, IRS-2, Akt-1, and the p85 subunit of PI-3K was significantly increased by estradiol, basal phospho p44/42 MAPK was significantly reduced. The data indicate that in addition to their classic actions, antiestrogens have major effects on IGF signaling pathways.