Antiestrogen ICI 182,780 decreases proliferation of insulin-like growth factor I (IGF-I)-treated MCF-7 cells without inhibiting IGF-I signaling.
Previous studies have suggested that antiestrogens inhibit MCF-7 cell proliferation by alteringthe expression or activity of components of the insulin-like growth factor I (IGF-I) signaling pathway, including IGF-I receptor, insulin receptor substrate 1, and phosphatidylinositol 3-kinase. In this report, we examine the effects of the pure antiestrogen ICI 182,780 (ICI) on various targets of IGF-I signaling in MCF-7 cells. ICI treatment led to decreases in the absolute levels of cyclin D1 and cyclin A expression, retinoblastoma protein phosphorylation, and DNA synthesis in IGF-I-treated cells. However, IGF-I retained the ability to induce these events in the presence of ICI, suggesting that ICI treatment did not completely block IGF-I signaling. Consistent with this suggestion, IGF-I-induced phosphorylation of extracellular signal-regulated kinase, AKT, and insulin receptor substrate 1 was unaffected by ICI treatment. Finally, transient expression of either constitutively active phosphatidylinositol 3-kinase or AKT was unable to induce proliferation in ICI-treated MCF-7 cells. Together, these results indicate that ICI can inhibit proliferation without blocking IGF-I signaling and suggest a model in which both estrogen receptor and IGF-I signaling regulate cell cycle components and are required for MCF-7 cell proliferation.
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA.
Hemant
H
Varma
Susan E
SE
Conrad
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D000077267:Fulvestrant; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011960:Receptors, Estrogen / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D019938:Cyclin D1; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D000077267:Fulvestrant; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C526292:IRS1 protein, human; C494918:AKT1 protein, human