Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7 cells

Zearalenone is a naturally occurring estrogenic contaminant of moldy feeds and is present in high concentrations in dairy products and cereals. Zearal enone was postulated to contribute to the overall estrogen load of women, b ut the mechanisms of its action are not known. We demonstrated that zearale none could stimulate the growth of estrogen receptor-positive human breast carcinoma cell line MCF-7. In addition, zearalenone functioned as an antiap optotic agent by increasing the survival of MCF-7 cell cultures undergoing apoptosis caused by serum withdrawal. Treatment of these cells with 100 nM zearalenone induced cell-cycle transit after increases in the expression of c-myc mRNA and cyclins D1, A, and B1 and downregulation of p27(Kip-1) G(1) /G(2)-phase kinase activity and phosphorylation of the retinoblastoma gene product was also evident. Flow cytometric analysis demonstrated entry of ce lls into the S and G(2)/M phases of the cell cycle, and phosphorylation of histone H3 occurred 36 h after zearalenone treatment. Ectopic expression of a dominant-negative p21(ras) completely abolished the zearalenone-induced DNA synthesis in these cells, and the specific inhibitor PD98059 for mitoge n/extracellular-regulated protein kinase kinase arrested S-phase entry indu ced by zearalenone. These data suggest that the mitogen-activated protein k inase signaling cascade is required for zearalenone's effects on cell-cycle progression in MCF-7 cells. Given the presence of this mycotoxin in cereal s, milk, and meat, the possibility that zearalenone is a potential promoter of breast cancer tumorigenesis should be investigated further. (C) 2001 Wi ley-Liss. Inc.