Role of IRS-1 signaling in insulin-induced modulation of estrogen receptors in breast cancer cells.
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 approximately 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.
Andò
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S
Dipartimento di Biologia Cellulare, Universita' degli Studi della Calabria, Cosenza, Italy. sando@diemme.it
Panno
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ML
Salerno
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M
Sisci
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D
Mauro
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L
Lanzino
M
M
Surmacz
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E
D001943:Breast Neoplasms / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology; D011972:Receptor, Insulin / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D017077:Culture Media, Conditioned; D006131:Growth Inhibitors; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D014443:Tyrosine; D004958:Estradiol; D011972:Receptor, Insulin