Type 1 IGF receptor in human breast diseases

Abstract

The first step of the action of IGF1 and IGF2 (IGFs) is their binding to membrane receptors. IGF binding sites have been characterized by competitive binding and cross-linking techniques in human breast cancer cell lines as well as in human breast cancers and in human benign breast diseases. IGF2 is a good competitor of¹²⁵I-IGF1 binding to IGF1-R; insulin competes but with a potency 1/100 lower than the IGF1 potency. Chemical cross-linking experiments revealed that the apparent molecular weight of the IGF1-binding sites is 130,000. Alpha IR-3, a murine monoclonal antibody against the IGF1-R, blocks IGF1-binding to this receptor. This antibody inhibits the IGF1-stimulated growth of breast cancer cells. Therefore, the IGF1 specific binding sites correspond to the previously described type 1 IGF receptors (IGF1-R) in normal tissues. Cross-linking experiments with labeled IGF2 resulted in a major band of apparent Mr 260,000–270,000 that was inhibited by unlabeled IGF2 but not by insulin, and corresponds to the type 2 IGF receptor; a second band of apparent Mr 130,000 was inhibited by excess IGFs and insulin (Type I receptor). The alpha-IR3 inhibition of the IGF2 mitogenic activity suggest that IGF1-R partially mediates the growth effect of IGF2 in these cells. We and others have demonstrated that most breast cancer cell lines contain IGF1-R. This is also the case in breast cancer biopsies in which histo-autoradiographic analyses allowed the localization of IGF1-R on the epithelial component. IGF1-R concentrations were positively correlated to estradiol and progesterone receptor concentrations. In our experience, the presence of IGF1-R is associated with a better prognosis. Finally, IGF1-R are found less frequently and at lower concentrations in benign breast diseases. These results suggest that IGF1-R could be a marker of the proliferative epithelial component within the tumor.