Results of recent studies in animal models of mammary carcinogenesis showed that the soybean isoflavone genistein is a chemopreventive agent. The objective of the present study was to determine whether soybean isoflavones can be used for the prevention of human breast carcinogenesis. Human adenocarcinoma cells that are either estrogen-receptor positive (such as MCF-7) or estrogen-receptor negative (such as MDA-MB-468) were used as our model system. Treatment of these cells with genistein concentrations of 15, 30, and 45 micromol/L resulted in cell growth inhibition, which was accompanied by the expression of maturation markers. Maturation was monitored by the induction of intracytoplasmic casein and lipids and the membrane protein intercellular adhesion molecule-1. These maturation markers were optimally expressed after 9 d of treatment with 30 mmol genistein/L. Both estrogen receptor-positive and -negative cells became differentiated in response to genistein treatments, suggesting that the antiestrogenic function of genistein is unrelated to the mechanism of cell differentiation. Daidzein, the other major isoflavone component of soybeans, did not induce differentiation in either MCF-7 or MDA-MB-468 cells. To explore the potential applications of this result, we used the nude mouse xenograft model of carcinogenesis. Treatment of either cell line with genistein before implantation into nude mice diminished the cells' tumorigenic potential. These data suggest that initiation of the differentiation program provides a protective effect against tumor growth in mouse xenografts.