Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinases / drug effects
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Estradiol / analogs & derivatives
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Estradiol / pharmacology
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Estrogen Antagonists / pharmacology
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Estrogens / metabolism*
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Female
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Fulvestrant
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Gene Expression Regulation, Neoplastic
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Humans
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Insulin Receptor Substrate Proteins
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Insulin-Like Growth Factor I / metabolism
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Insulin-Like Growth Factor I / pharmacology
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Intracellular Signaling Peptides and Proteins
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Mammary Neoplasms, Experimental / metabolism
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Mice
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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Receptor, Insulin / genetics
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Receptor, Insulin / metabolism
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Receptors, Estrogen / metabolism
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Receptors, Somatomedin / genetics
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Receptors, Somatomedin / metabolism
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Signal Transduction
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Somatomedins / metabolism*
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Survival Rate
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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Estrogen Antagonists
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Estrogens
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IRS1 protein, human
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IRS2 protein, human
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, mouse
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Irs2 protein, mouse
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Phosphoproteins
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Receptors, Estrogen
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Receptors, Somatomedin
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Somatomedins
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Fulvestrant
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Estradiol
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Insulin-Like Growth Factor I
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Receptor, Insulin
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Calcium-Calmodulin-Dependent Protein Kinases