Insulin-like growth factors (IGFs) regulate normal growth and development. In breast cancer, they stimulate cell proliferation, cell migration and inhibit apoptosis. The IGF signal transduction pathway is, therefore, a potential therapeutic target in the treatment of breast cancer 12. Inhibitors of the IGF pathway may be effective in the treatment of breast cancer with de novo or acquired endocrine resistance. We have studied IGF signalling in oestrogen nonresponsive MDA-MB-231, HBL-100 and BT-20 breast cancer cell lines as models of endocrine resistant breast cancer. Oestrogen responsive MCF-7 cells were also studied.

Components of the IGF signalling pathway, type I IGF Receptor (IGF1R), IRS-1, IRS-2, and the three Shc isoforms, were expressed at varying levels, demonstrating a range of phenotypes in the breast cancer cells. IRS-1 is expressed in a truncated form in the BT-20 cells as an antibody to the C-terminus is unable to detect the protein.

IGF-1 activated IGF1R, IRS-1, MAP kinase and Akt in the MCF-7, MDA-MB-231 and HBL-100 cell lines. IGF-1 stimulated phosphorylation of IGF1R in BT-20 cells but did not alter the level of activation of IRS-1, MAP kinase or Akt. The MEK1/2 inhibitor (PD 98059) and the PI-3 kinase inhibitor (LY 294002) decreased the level of phosphorylation of MAP kinase and Akt in BT-20 cells. A phosphospecific antibody to tyrosine 896, the Grb2 SH2 binding site, shows that IRS-1 is constitutively phosphorylated in BT-20 cells.

IGF-1 inhibited staurosporine-induced apoptosis in MCF-7, MDA-MB-231 and HBL-100 cells but not in BT-20 cells. Inhibition of the IGF signalling pathways with PD 98059 and LY 294002 sensitise MDA-MB-231 cells to staurosporine-induced apoptosis. IGF-1 stimulated growth in MCF-7 and MDA-MB-231 cells but not in BT-20 cells.

Expression and activation of IGF signalling proteins vary among the oestrogen nonresponsive cells. These differences will affect the response of breast cancer cells to IGF targeted therapy. BT-20 cells provide a useful model for constitutive IRS-1 phosphorylation which is reported to occur in breast tumours 3.