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. Zearalenone was postulated to contribute to the overall estrogen load of women, but the mechanisms of its action are not known. We demonstrated that zearalenone could stimulate the growth of estrogen receptor-positive human breast carcinoma cell line MCF-7. In addition, zearalenone functioned as an antiapoptotic 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 cells 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 mitogen/extracellular-regulated protein kinase kinase arrested S-phase entry induced by zearalenone. These data suggest that the mitogen-activated protein kinase signaling cascade is required for zearalenone's effects on cell-cycle progression in MCF-7 cells. Given the presence of this mycotoxin in cereals, milk, and meat, the possibility that zearalenone is a potential promoter of breast cancer tumorigenesis should be investigated further. Mol. Carcinog. 30:88-98, 2001.
Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee 37920, USA.
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Ahamed
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Foster
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Bukovsky
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Wimalasena
D000256:Adenoviridae / Q000235:genetics; D017304:Annexin A5 / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005562:Formazans; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D013778:Tetrazolium Salts; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins; D015025:Zearalenone / Q000494:pharmacology*
D017304:Annexin A5; D018797:Cell Cycle Proteins; D004968:Estrogens, Non-Steroidal; D005562:Formazans; D008869:Microtubule-Associated Proteins; D013778:Tetrazolium Salts; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C079782:MTT formazan; D015025:Zearalenone; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D001973:Bromodeoxyuridine