LITHIUM-STIMULATED PROLIFERATION AND ALTERATION OF PHOSPHOINOSITIDE METABOLITES IN MCF-7 HUMAN BREAST-CANCER CELLS

Lithium, which is used to treat bipolar psychiatric disorders, can sti mulate proliferation of a number of cells in tissue culture. Prolifera tion of MCF-7 human breast cancer cells, which also respond to EGF and estrogens, was stimulated by LiCl (1-5 mM) within the concentration r ange that is encountered during human therapy with lithium. Stimulatio n of growth was specific for lithium; rubidium, potassium, and sodium showed no such effect. In the presence of antiestrogen, lithium stimul ated the growth of hormone-dependent breast cancer cells MCF-7, ZR-75- 1, and T47D but not hormone-independent MDA-MB-231 cells or an estroge n-independent clone of MCF-7 cells. Lithium-stimulated proliferation w as limited by cytotoxicity which could be moderated by added potassium chloride (5-20 mM) in the medium. Each of the mitogens lithium, 17 be ta-estradiol, and EGF increased the rate of uptake of myo-inositol int o MCF-7 cells. Whether normalized to inositol lipids, to protein, or t o DNA, steady-state levels of inositol phosphates were elevated by eac h of the mitogens including lithium, which inhibits the breakdown of i nositol phosphates in the phosphoinositide signaling pathway. These da ta indicate that therapeutic concentrations of lithium can stimulate t he proliferation of human breast cancer cells by a mechanism that may involve the phosphoinositide pathway. (C) 1995 Wiley-Liss, Inc.