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 estrogen enhances IGF signaling by inducing expression of three key IGF-regulatory molecules, the type 1 IGF receptor (IGFR1) and its downstream signaling molecules, insulin receptor substrate (IRS)-1 and IRS-2. Estrogen induction of IGFR1 and IRS expression resulted in enhanced tyrosine phosphorylation of IRS-1 after IGF-I stimulation, followed by enhanced mitogen-activated protein kinase activation. To examine whether these pathways were similarly activated in vivo, we examined MCF-7 cells grown as xenografts in athymic 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 shown that high IRS-1 expression is an indicator of early disease recurrence in ER-positive human primary breast tumors. Taken together, these data not only reinforce the concept of cross-talk between IGF- and ER-signaling pathways, but indicate that IGF molecules may be critical regulators of estrogen-mediated growth and breast cancer pathogenesis.
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D015996:Survival Rate; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured