Ahamed S, Foster J S, Bukovsky A, Wimalasena J
Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee 37920, USA.
Mol Carcinog. 2001 Feb;30(2):88-98. doi: 10.1002/1098-2744(200102)30:2<88::aid-mc1017>3.0.co;2-e.
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.
玉米赤霉烯酮是发霉饲料中天然存在的一种具有雌激素活性的污染物，在乳制品和谷物中含量很高。曾有人推测玉米赤霉烯酮会增加女性体内的雌激素总量，但其作用机制尚不清楚。我们证明，玉米赤霉烯酮能够刺激雌激素受体阳性的人乳腺癌细胞系MCF-7生长。此外，玉米赤霉烯酮通过提高血清饥饿诱导凋亡的MCF-7细胞培养物的存活率，发挥抗凋亡剂的作用。用100 nM玉米赤霉烯酮处理这些细胞，可使c-myc mRNA以及细胞周期蛋白D1、A和B1的表达增加，p27（Kip-1）下调，从而诱导细胞周期进程。G（1）/G（2）期激酶活性以及视网膜母细胞瘤基因产物的磷酸化也很明显。流式细胞术分析表明，细胞进入细胞周期的S期和G（2）/M期，玉米赤霉烯酮处理36小时后发生组蛋白H3磷酸化。显性负性p21（ras）的异位表达完全消除了玉米赤霉烯酮诱导的这些细胞中的DNA合成，丝裂原/细胞外调节蛋白激酶激酶的特异性抑制剂PD98059阻止了玉米赤霉烯酮诱导的S期进入。这些数据表明，丝裂原活化蛋白激酶信号级联反应是玉米赤霉烯酮对MCF-7细胞周期进程发挥作用所必需的。鉴于谷物、牛奶和肉类中存在这种霉菌毒素，玉米赤霉烯酮是否为乳腺癌肿瘤发生的潜在促进因素，这一可能性应进一步研究。《分子致癌作用》30:88 - 98，2001年。
