Studies of the mechanisms of action of the cancer chemopreventive agent genistein

The discrepancy in incidence of breast cancer between the Western world and South East Asia has been associated with the high content in Asian diets of chemopreventive foodstuffs such as soy. Genistein, a major constituent of soy, can both inhibit and stimulate cell growth, depending on concentration. Whilst some biochemical properties of genistein are well known, such as inhibition of tyrosine kinases and DNA topoisomerase II, the mechanisms by which it regulates cell growth are unclear.;In order to explore generic features of the modulation of human breast cell growth by genistein, its effects on cell lines MCF-7, ZR-75.1, T47-D, MDA-MB 468, MDA-MB 231 and HBL 100 were compared. Genistein at 1 M stimulated growth only in MCF-7 cells, whilst at 10 M it arrested the growths of all six cell types. However, in T47-D and HBL 100 cells, genistein only inhibited growth in medium with reduced (2%) foetal calf serum. Genistein induced apoptosis only in MDA-MB 468 cells and arrested cells in the G phase transition of the cell cycle in all cell lines, except ZR-75.1 cells.;Cells differed in their susceptibility towards inhibition by genistein of phorbol ester-induced proto-oncogene c-Fos levels, transcription factor activator protein-1 (AP-1) activity, AP-1 DNA-binding activity and extracellular signal regulated kinase (ERK) activation. Genistein augmented anisomycin-induced protein levels of the proto-onocogene c-Jun in ZR 75.1 and MCF-7 cells, but inhibited c-Jun phosphorylation.;The results suggest that induction of apoptosis, G2 cells arrest, inhibition of c-Fos expression, AP-1 transactivation and binding, and ERK phosphorylation may contribute to the growth-inhibitory effect of genistein in some breast cell types, but none of these effects of genistein constitute a generic mode of growth-arresting action.