OVEREXPRESSION OF MEMBRANE GLYCOPROTEIN PC-1 IN MDA-MB231 BREAST-CANCER CELLS IS ASSOCIATED WITH INHIBITION OF INSULIN-RECEPTOR TYROSINE KINASE-ACTIVITY

MDA-MB231 human breast cancer cells are unresponsive to insulin and co ntain a glycoprotein inhibitor of insulin-stimulated insulin receptor (IR) tyrosine kinase activity. Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients an d transfected cells indicate that overexpression of membrane glycoprot ein PC-1 reduces IR tyrosine kinase activity. In the present study, we measured PC-1 content and activity in MDA-MB231 and four other human breast cancer cell lines. We observed that PC-1 expression was 3- to 3 0-fold higher in MDA-MB231 cells when compared with the other breast c ell lines. Wheat germ agglutinin extracts of MDA-MB231 cells inhibited IR tyrosine kinase activity. Treatment of these extracts with an anti body to PC-1 significantly reduced their ability to inhibit insulin-st imulated IR tyrosine kinase activity. In addition, when cell clones wi th different PC-1 activity were selected from MDA-MB231 cells, we foun d an inverse correlation (r = -0.741, P = 0.006) between the PC-1 acti vity and the insulin-stimulated IR autophosphorylation. A similar inve rse correlation was observed in cell clones derived from the insulin-r esponsive breast cancer cell line MCF-7. By both immunoprecipitation a nd cross-linking studies we found PC-1 to be associated with IR. These studies indicate, therefore, that overexpression of PC-1 in A MDA-MB2 31 cells may account, at least in part, for the reduced IR tyrosine ki nase activity and suggest that PC-1 is a specific modulator of the IR activity in breast cancer cells.