Inhibition of insulin-like growth factor signaling pathways in mammary gland by pure antiestrogen ICI 182,780.
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.
Chan
T W
TW
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610.
Pollak
M
M
Huynh
H
H
D000818:Animals; D001284:Atrophy; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen / Q000032:analysis; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013002:Somatomedins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology
D004965:Estrogen Antagonists; D055504:Insulin Receptor Substrate Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D019394:Ki-67 Antigen; D010750:Phosphoproteins; D012333:RNA, Messenger; D013002:Somatomedins; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases