MITOGENIC SIGNALING OF INSULIN-LIKE-GROWTH-FACTOR-I IN MCF-7 HUMAN BREAST-CANCER CELLS REQUIRES PHOSPHATIDYLINOSITOL 3-KINASE AND IS INDEPENDENT OF MITOGEN-ACTIVATED PROTEIN-KINASE

Addition of insulin-like growth factor I (IGF-I) to quiescent breast t umor-derived MCF-7 cells causes stimulation of cyclin D1 synthesis, hy perphosphorylation of the retinoblastoma protein pRb, DNA synthesis, a nd cell division. All of these effects are independent of the mitogen- activated protein kinase (MAPK) pathway since none of them is blocked by PD098059, the specific inhibitor of the MAPK activating kinase MEK1 , This observation is consistent with the finding that the phorbol est er 12-O-tetradecanoylphorbol-13-acetate (TPA), a strong inducer of MAP K activity in MCF-7 cells, effectively inhibits proliferation, The ant i-proliferative effect of TPA in these cells may be accounted for, at least in part, by the MAPK-dependent stimulation of the synthesis of p 21(WAF1/CIP1), inhibitor of cyclin/cyclin-dependent kinase complexes. In contrast, all of the observed stimulatory effects of IGF-I on cell cycle progression, cyclin D1 synthesis, and pRb hyperphosphorylation w ere blocked by the specific phosphatidylinositol 3-kinase inhibitor LY 294002, suggesting that phosphatidylinositol 3-kinase activity but not MAPK activity is required for transduction of the mitogenic IGF-I sig nal in MCF-7 cells.