RELATIONSHIP OF GROWTH STIMULATED BY LITHIUM, ESTRADIOL, AND EGF TO PHOSPHOLIPASE-C ACTIVITY IN MCF-7 HUMAN BREAST-CANCER CELLS

Lithium-stimulated MCF-7 cell proliferation was compared to proliferat ion stimulated by other mitogens for this cell line-estradiol (E(2)) a nd epidermal growth factor (EGF) - and lithium was found to be effecti ve within a narrow concentration range. Mitogenic effects of lithium o n proliferation stimulated by E(2) and EGF were additive below maximum , but were not synergistic. The phosphoinositide pathway is a cell sig naling system involved in cell proliferation, within which phospholipa se C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphat e [PtdIns(4,5)P-2] leads to the production of the second messengers in ositol-1,4,5-trisphosphate [Ins(1,4,5)P-2] and diacylglycerol (DAG), a s well as to calcium mobilization. At mitogen concentrations which max imally stimulated cell growth, estradiol stimulated both growth and PL C activity, while EGF and lithium stimulated cell growth but had littl e effect on the activity of the enzyme. Dose-responses with EGF reveal ed that a low concentration (0.1 ng/ml, 0.017 nM) of EGF appeared to s timulate both PLC activity and cell growth, but that higher concentrat ions of EGF which stimulated greater proliferation inhibited PLC activ ity. Steady-state levels of inositol phosphates including inositol tri sphosphate were increased by all three mitogens. In growth assays, the phorbol ester phorbol 12-myristate-13-acetate (PMA), which mimics the actions of DAG, stimulated some cell growth, but dioctanoylglycerol, an additional DAG analog, and the calcium ionophore A23187, alone or w ith the DAG analogs, had no effect. These results suggest that PLC-med iated PtdIns(4,5)P-2 hydrolysis is not primarily associated with signa ling proliferation by lithium or EGF in MCF-7 breast cancer cells.