Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines

Oncogene. 2001 Nov 1;20(50):7318-25. doi: 10.1038/sj.onc.1204920.


Insulin-like growth factors (IGFs) regulate breast cancer cell proliferation, protect cells from apoptosis, and enhance metastasis. In this study, we examined the IGF signaling pathway in two breast cancer cell lines selected for metastatic behavior. LCC6 was selected for growth as an ascites tumor in athymic mice from parental MDA-MB-435 cells (435P). The MDA-231BO cell line was derived from osseous metastases that formed after intracardiac injection of the MDA-MB-231 cell line in athymic mice. Compared to the parental cell lines, IGF-I treatment enhanced IRS-2 phosphorylation over IRS-1 in the metastatic variants. IGF-I stimulated cell migration in the variant cells, but not in the parental cells. To determine the role for IRS-2 in IGF-mediated motility, we transfected MDA-231BO cells with an anti-sense IRS-2 construct. Transfected cells had decreased levels of IRS-2 with diminished IGF-mediated motility and anchorage independent growth when compared to control cells. However, adherence to fibronectin was enhanced in the transfected cells compared to MDA-231BO cells. Our data show that breast cancer cells selected for metastatic behavior in vivo have increased IRS-2 activation and signaling. In these cells, IGF-I enhances cell adhesion and motility suggesting that IRS-2 may mediate these aspects of the malignant phenotype.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Breast Neoplasms / pathology*
  • Cell Adhesion
  • Cell Division
  • Cell Movement / physiology
  • DNA, Antisense / genetics
  • Female
  • Humans
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / pathology*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, IGF Type 1 / drug effects
  • Receptor, IGF Type 1 / physiology
  • Recombinant Fusion Proteins / physiology
  • Selection, Genetic
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured / cytology


  • DNA, Antisense
  • IRS2 protein, human
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Neoplasm Proteins
  • Phosphoproteins
  • Recombinant Fusion Proteins
  • Insulin-Like Growth Factor I
  • Protein-Tyrosine Kinases
  • Receptor, IGF Type 1