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

Robert Calaluce, Mark W. Kunkel, George S. Watts, Monika Schmelz, Junshan Hao, Jean Barrera, Mary Gleason-Guzman, Robert Isett, Mark Fitchmun, G. Tim Bowden, Anne E. Cress, Bernard W. Futscher, Raymond B. Nagle

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

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 p27Kip-1. G1/G2-phase kinase activity and phosphorylation of the retinoblastoma gene product was also evident. Flow cytometric analysis demonstrated entry of cells into the S and G2/M phases of the cell cycle, and phosphorylation of histone H3 occurred 36 h after zearalenone treatment. Ectopic expression of a dominant-negative p21ras 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.

Original languageEnglish (US)
Pages (from-to)88-98
Number of pages11
JournalMolecular Carcinogenesis
Volume30
Issue number2
DOIs
StatePublished - Mar 15 2001

Keywords

  • Apoptosis
  • Breast cancer
  • Mycoestrogen
  • Nongenomic activity

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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