The antiestrogen ICI 182,780 inhibits proliferation of human breast cancercells by interfering with multiple, sequential estrogen-regulated processes required for cell cycle completion

Antiestrogens are widely used for breast cancer treatment, where they act p rimarily by inhibiting the mitogenic action of estrogens on tumor cells. Th e effects of the pure antiestrogen ICI 182,780 on estrogen-regulated cell c ycle phase-specific events were investigated here in synchronously cycling human breast cancer (HBC) cells. In early G(1)-arrested MCF-7 or ZR-75.1 ce lls, 17 beta-estradiol (E2) induces rapid activation of the cyclin/Cdk/pRb pathway, as demonstrated by D-type G(1) cyclins accumulation during the fir st few hours of hormonal stimulation, followed by sequential accumulation o f E, A and B1 cyclins and progressive pRb phosphorylation, as cells progres s through the cell cycle. When added to quiescent cells together with E2, I CI 182,780 prevents all of the above hormonal effects. Interestingly, in mi d-G(1) cells (2-8 h into estrogen stimulation) the antiestrogen causes rapi d reversal of hormone-induced D-type cyclins accumulation and pRb phosphory lation, and still fully inhibits G(1)-S transition rate, while in late-G(1) cells it does not prevent S phase entry but still inhibits significantly D NA synthesis rate, S-phase cyclins accumulation and pRb hyperphosphorylatio n. These results indicate that pure antiestrogens prevent multiple estrogen -induced cell cycle-regulatory events, each timed to allow efficient G(1) c ompletion, G(1)-S transition, DNA synthesis and cell cycle completion. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.