Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

Br J Cancer. 2006 Nov 6;95(9):1220-8. doi: 10.1038/sj.bjc.6603354. Epub 2006 Oct 17.


Activation of the type I insulin-like growth factor receptor (IGF-IR) regulates several aspects of the malignant phenotype, including cancer cell proliferation and metastasis. Phosphorylation of adaptor proteins downstream of IGF-IR may couple IGF action to specific cancer phenotypes. In this study, we sought to determine if insulin receptor substrate-1 and -2 (IRS-1 and -2) mediate distinct biological effects in breast cancer cells. Insulin receptor substrate-1 and IRS-2 were expressed in T47D-YA breast cancer cells, which lack IRS-1 and -2 expression, yet retain functional IGF-IR. In the absence of IRS-1 and -2 expression, IGF-IR activation was unable to stimulate proliferation or motility in T47D-YA cells. Expression of IRS-1 resulted in IGF-I-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-I-stimulated motility, but did not stimulate proliferation. The alphaIR-3, an inhibitor of the IGF-IR, was unable to affect these IGF-stimulated phenotypes unless IRS-1 or -2 was expressed. Thus, IGF-IR alone is unable to regulate important breast cancer cell phenotypes. In these cells, IRS proteins are required for and mediate distinct aspects of IGF-IR-stimulated behaviour. As multiple agents targeting the IGF-IR are currently in early clinical trials, IRS expression should be considered as a potential biomarker for IGF-IR responsiveness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Breast Neoplasms / physiopathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Gene Expression / drug effects
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / pharmacology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • RNA Interference
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / immunology
  • Receptor, IGF Type 1 / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Transfection


  • Antibodies, Monoclonal
  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1