Enhancement of insulin-like growth factor signaling in human breast cancer: Estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo

Cross-talk between insulin-like growth factor (IGF)- and estrogen receptor (ER)-signaling pathways results in synergistic growth. We show here that es trogen enhances IGF signaling by inducing expression of three key IGF- regu latory molecules, the type I IGF receptor (IGFR1) and its downstream signal ing molecules, insulin receptor substrate (IRS)-1 and IRS-2. Estrogen induc tion of IGFR1 and IRS expression resulted in enhanced tyrosine phosphorylat ion of IRS-1 after IGF-I stimulation, followed by enhanced mitogen-activate d protein kinase activation. To examine whether these pathways were similar ly activated in vivo, we examined MCF-7 cells grown as xenografts in athymi c mice. IRS-1 was expressed at high levels in estrogen-dependent growth of MCF-7 xenografts, but withdrawal of estrogen, which decreased tumor growth, resulted in a dramatic decrease in IRS-1 expression. Finally, we have show n that high IRS-1 expression is an indicator of early disease recurrence in ER-positive human primary breast tumors. Taken together, these data not on ly reinforce the concept of cross-talk between IGF- and ER-signaling pathwa ys, but indicate that IGF molecules may be critical regulators of estrogen- mediated growth and breast cancer pathogenesis.