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 regulate s the growth of hormone-responsive breast cancer cells. For example, in the MCF-7 human breast cancer cell line, insulin upregulates estrogen receptor (ER) content and binding capacity. Since the insulin receptor (IR) substra te 1 (IRS-1) is one of the core signaling elements transmitting mitogenic a nd metabolic effects of insulin, we investigated whether IRS-1 is also requ ired 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 decre ased levels (by similar to 80%) of IRS-1 due to the expression of IRS-1 ant isense 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-r egulation of ER protein expression and binding capacity; and (4) loss of in sulin-induced regulation of ER tyrosine phosphorylation. In conclusion, the data confirm the existence of the IR-ER cross-talk and suggest that IRS-l- dependent signaling may contribute to the negative regulation of the ER exp ression and function in MCF-7 cells. (C) 1998 Academic Press.