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

Mol Endocrinol. 1999 May;13(5):787-96. doi: 10.1210/mend.13.5.0274.


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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estrogen Antagonists / pharmacology
  • Estrogens / metabolism*
  • Female
  • Fulvestrant
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism
  • Signal Transduction
  • Somatomedins / metabolism*
  • Survival Rate
  • Transplantation, Heterologous
  • Tumor Cells, Cultured


  • Estrogen Antagonists
  • Estrogens
  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Phosphoproteins
  • Receptors, Estrogen
  • Receptors, Somatomedin
  • Somatomedins
  • Fulvestrant
  • Estradiol
  • Insulin-Like Growth Factor I
  • Receptor, Insulin
  • Calcium-Calmodulin-Dependent Protein Kinases