Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line

Estrogens can stimulate the proliferation of estrogen-responsive breast can cer cells by increasing their proliferative response to insulin-like growth factors. The mechanism underlying the increased proliferation could involv e the induction of components of the insulin-like growth factor signal tran sduction pathway by estrogen, In this study we have examined the regulation of the expression of insulin receptor substrate-1, a major intracellular s ubstrate of the type I insulin-like growth factor receptor tyrosine kinase, Estradiol increased insulin receptor substrate-1 mRNA and protein levels a t concentrations consistent with a mechanism involving the estrogen recepto r. Insulin receptor substrate-1 was not induced significantly by the anties trogens tamoxifen and ICI 182,780, but they inhibited the induction of insu lin receptor substrate-1 by estradiol. Analysis of tyrosine-phosphorylated insulin receptor substrate-1 showed that the highest levels were found in c ells stimulated by estradiol and insulin-like growth factor-I, whereas low levels were found in the absence of estradiol irrespective of whether type I insulin-like growth factor ligands were present. Insulin receptor substra te-2, -3, and -4 were not induced by estradiol. These results suggest that estrogens and antiestrogens may regulate cell proliferation by controlling insulin receptor substrate-1 expression, thereby amplifying or attenuating signaling through the insulin-like growth factor signal transduction pathwa y.