Role of IRS-1 Signaling in Insulin-Induced Modulation of Estrogen Receptors in Breast Cancer Cells

• Published in: Biochemical and biophysical research communications 1998-12, Vol.253 (2), p.315-319
• Main Authors: Ando', Sebastiano, Panno, Maria-Luisa, Salerno, Michele, Sisci, Diego, Mauro, Loredana, Lanzino, Marilena, Surmacz, Ewa
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - metabolism; Culture Media, Conditioned - pharmacology; Down-Regulation - physiology; Estradiol - pharmacology; Growth Inhibitors - physiology; Humans; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Phosphoproteins - physiology; Phosphorylation; Protein Binding - physiology; Receptor Cross-Talk - physiology; Receptor, Insulin - metabolism; Receptors, Estrogen - biosynthesis; Receptors, Estrogen - drug effects; Receptors, Estrogen - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Tumor Cells, Cultured; Tyrosine - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1998.9330

Cross-talk between steroid hormones and polypeptide growth factors regulates the growth of hormone-responsive breast cancer cells. For example, in the MCF-7 human breast cancer cell line, insulin up-regulates estrogen receptor (ER) content and binding capacity. Since the insulin receptor (IR) substrate 1 (IRS-1) is one of the core signaling elements transmitting mitogenic and metabolic effects of insulin, we investigated whether IRS-1 is also required for the insulin-induced function of the ER. The effects of insulin on the ER were compared in MCF-7 cells and MCF-7-derived cell lines with decreased levels (by ∼80%) of IRS-1 due to the expression of IRS-1 antisense RNA. The severe IRS-1 deficiency in MCF-7 cells was associated with (1) reduced mitogenic response to 20 ng/ml insulin and 10% calf serum (CS), but not to 1 nM estradiol (E2); (2) loss of insulin-E2 synergism; (3) up-regulation of ER protein expression and binding capacity; and (4) loss of insulin-induced regulation of ER tyrosine phosphorylation. In conclusion, the data confirm the existence of the IR–ER cross-talk and suggest that IRS-1-dependent signaling may contribute to the negative regulation of the ER expression and function in MCF-7 cells.