Down-regulation of p21WAF1/CIP1 or p27KiP1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells

Sandrine Cariou, Jeffrey C.H. Donovan, W. M. Flanagan, Andrea Milic, Nandita Bhattacharya, Joyce M. Slingerland

Research output: Contribution to journalArticle

192 Scopus citations

Abstract

Estrogens and antiestrogens influence the G1 phase of the cell cycle. In MCF-7 breast cancer cells, estrogen stimulated cell cycle progression through loss of the kinase inhibitor proteins (KIPs) p27 and p21 and through G1 cyclin-dependent kinase (cdk) activation. Treatment with antiestrogen drugs, Tamoxifen or ICI 182780, caused cell cycle arrest, with up-regulation of both p21 and p27 levels, an increase in their binding to cyclin E-cdk2, and 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 antiestrogen-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 entrance. These data demonstrate that depletion of either p21 or p27 can mimic estrogen-stimulated cell cycle activation and indicate that both of these KIPs are critical mediators of the therapeutic effects of antiestrogens in breast cancer.

Original languageEnglish (US)
Pages (from-to)9042-9046
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number16
DOIs
StatePublished - Aug 1 2000
Externally publishedYes

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