Biphasic effects of zeranol on the growth of estrogen receptor-positive human breast carcinoma cells

Zeranol (alpha-zearalanol) is a metabolite of the mycoestrogen zearalenone, and is used as a growth promoter of livestock due to its strong estrogenic activity. In the present study, we investigated the effects of zeranol on the growth of estrogen receptor (ER)-positive and -negative human breast carcinoma cells in vitro, and the molecules involved. At low concentrations, zeranol accelerated the growth of ER-positive MCF-7 and KPL-1 human breast carcinoma cells, but did not affect the growth of ER-negative MDA-MB-231 cells. At high concentrations, zeranol suppressed the growth of both ER-positive and -negative human breast carcinoma cells. The acceleration of ER-positive cell growth by low-dose zeranol involved the down-regulation of p21Cip1 (a cyclin-dependent kinase inhibitor), which resulted in cell cycle progression. High-dose zeranol induced the formation of a sub-G1 fraction and the up-regulation of the apoptosis stimulator p53, suggesting the induction of apoptosis. Thus, zeranol exerted dose-dependent biphasic effects on ER-positive human breast carcinoma cells, accelerating cell growth at low concentrations and inducing apoptosis at high concentrations.