Antiestrogen ICI 182,780 decreases proliferation of insulin-like growth factor I (IGF-I)-treated MCF-7 cells without inhibiting IGF-I signaling.

Abstract

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.