EFFECTS OF TYROSINE KINASE INHIBITORS ON THE PROLIFERATION OF HUMAN BREAST-CANCER CELL-LINES AND PROTEINS IMPORTANT IN THE RAS SIGNALING PATHWAY

Breast cancers frequently over-express a number of growth factor recep tors. In addition, elevated src family kinase activity is present in a percentage of these neoplasms and has been implicated in signal trans duction in these cells. Therefore, inhibiting tyrosine kinase activity is a potential approach for treating these tumors. Utilizing the SKBR 3 and MCF-7 breast cancer cell lines, we evaluated the effects of broa dly targeting growth factor receptor and cytoplasmic tyrosine kinases with tyrosine kinase inhibitors (herbimycin A and genistein) to inhibi t proliferation. We also evaluated these inhibitors' effects on protei ns that regulate ras function, which is a convergence point for signal ing through both src family kinases and a number of growth factor rece ptors with tyrosine kinase activity (e.g., epidermal growth factor and erbB-2 receptors). We specifically evaluated whether these compounds affected 2 recently discovered proteins involved in controlling ras fu nction: Shc, which is tyrosine-phosphorylated by src and activated gro wth factor receptors, and Grb-2, which mediates signal transduction fr om activated growth factor receptors through ras. We evaluated their e ffects on tyrosine phosphorylation of Shc, binding of Grb-2 to She and MAP kinase activity. Both cell lines were inhibited in a dose-depende nt manner by each compound. This was accompanied by decreased She tyro sine phosphorylation, Shc's association with Grb-2 and MAP kinase acti vity. Thus, tyrosine kinase inhibitors can inhibit proliferation of br east cancer cells, accompanied by inhibition of signal transduction st eps potentially mediated through ras. Tyrosine kinase inhibitors might , therefore, be useful for the treatment of breast cancer. (C) 1996 Wi ley-Liss, Inc.