Induction of apoptosis in mammary gland by a pure anti-estrogen ICI 182780

The antiestrogen, ICI 182780 (ICI) proves to be clinically useful for the t reatment of estrogen receptor positive breast tumours. We report the assess ment of the in vivo and in vitro effects of ICI on apoptosis of breast epit helial cells. In vivo, administration of rats with ICI for 3 weeks resulted in a reduction in the size of the lobular structures with the rate of mamm ary epithelial apoptosis equivalent to 10, 35 and 45% on treatment with 1, 1.5 and 2 mg ICI per kg body weight, respectively. Concomitantly, these tre atment led to a 2.0-, 2.2- and 2.5-fold increase in Bax. Similar elevations were also observed in Bad levels which increased 1.7-, 2.6- and 2.7-fold r espectively in the ICI treatment as compared to controls. This also resulte d in a dose dependent decrease in Bcl-2 and Bcl-x(L) protein expressions. G rowth inhibition and induction of apoptosis were also observed in the MCF-7 cells following in vitro treatment with ICI. This is closely associated wi th [1] the down-regulation of Bcl-2 and Bcl-x(L) proteins and [2] upregulat ion of Bax and Bad, whose gene products are known to be involved the regula tion of apoptosis in mammalian cells. Stable over-expression of Bcl-2 resul ted in protection of MCF-7 cells from apoptosis and growth inhibitory effec ts of ICI. Conversely, reduction of Bcl-2 by antisense transfection make MC F-7 cells more sensitive to ICI-induced growth inhibition and apoptosis. Th ese findings suggest that modulation of Bax, Bcl-x(L), Bcl-2 and Bad protei ns by ICI may be, in part, responsible for the anti-proliferative and apopt otic effect of ICI seen clinically and in animal models.