REGULATION OF C-FOS TRANSCRIPTION BY CHEMOPREVENTIVE ISOFLAVONOIDS AND LIGNANS IN MDA-MB-468 BREAST-CANCER CELLS

Isoflavonoids and lignans are diet constituents with chemopreventive p roperties. We compared the ability of the isoflavonoids genistein and equol, the lignans enterodiol, enterolactone and nordihydroguaiaretic acid (NDGA) and the lignan metabolite methyl p-hydroxyphenyllactate to interfere with mitogenic and tumour promotional signal transduction p athways. Their effects on c-fos mRNA levels after induction by either epidermal growth factor (EGF) or the tumour promoting phorbol ester 12 -O-tetradecanoylphorbol-13-acetate (TPA) was measured in human breast cancer-derived MDA-MB-468 cells. Of the six agents, only genistein dec reased EGF-induced, c-fos transcription (by 63% compared to control at 100 mu mol/l). In contrast, both genistein and equol at 100 mu mol/l decreased TPA-induced c-fos levels, by 75 and 67%, respectively. NDGA and methyl p-hydroxyphenyllactate did not inhibit TPA mediated c-fos t ranscription and enterolactone and enterodiol had only a weak inhibito ry effect. NDGA at 0.1-10 mu mol/l increased c-fos mRNA levels. None o f the agents inhibited protein kinase C and only genistein inhibited E GF receptor-linked protein tyrosine kinase obtained from MDA-MB-468 ce lls, with an IC50 Of 60 mu mol/l. NDGA and genistein arrested cell col ony formation potently, genistein was 15-fold more growth-inhibitory t han equol. The results suggest that both genistein and equol interfere similarly with TPA-induced signal transduction pathways. Inhibition b y genistein of EGF-induced c-fos mRNA transcription is probably relate d to its interruption of EGF receptor-linked protein tyrosine kinase, whereas genistein-induced growth arrest is not. If ability to antagoni se phorbol ester effects is important for chemopreventive efficacy, eq uol and genistein might be equi-efficacious chemopreventors, whereas e nterolactone, enterodiol and NDGA should be much less potent. If phorb ol ester antagonism together with antimitogenic activity determine opt imal chemopreventive activity of this type of agent, genistein would b e more potent than equol. (C) 1998 Elsevier Science Ltd. All rights re served.