Down-regulation of p21(WAF1/CIP1) or p27(Kip1) abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells

Estrogens and antiestrogens influence the G(1) phase of the cell cycle. In MCF-7 breast cancer cells, estrogen stimulated cell cycle progression throu gh loss of the kinase inhibitor proteins (KIPs) p27 and p21 and through G(1 ) cyclin-dependent kinase (cdk) activation. Treatment with antiestrogen dru gs, Tamoxifen or ICI 182780, caused cell cycle arrest, with up-regulation o f both p21 and p27 levels, an increase in their binding to cyclin E-cdk2, a nd kinase inhibition. The requirement for these KIPs in the arrests induced by estradiol depletion or by antiestrogens was investigated with antisense , Antisense inhibition of p21 or p27 expression in estradiol-depleted or an tiestrogen-arrested MCF-7 led to abrogation of cell cycle arrest, with loss of cyclin E-associated KIPs, activation of cyclin E-cdk2, and S phase entr ance. These data demonstrate that depletion of either p21 or p27 can mimic estrogen-stimulated cell cycle activation and indicate that both of these K IPs are critical mediators of the therapeutic effects of antiestrogens in b reast cancer.