Down-Regulation of p21WAF1/CIP1or p27Kip1Abrogates Antiestrogen-Mediated Cell Cycle Arrest in Human Breast Cancer Cells

Estrogens and antiestrogens influence the G1phase 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 G1cyclin-dependent kinase (cdk) activation. Treatment with antiestrogen drugs, Ta...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 97; no. 16; pp. 9042 - 9046
Main Authors Cariou, Sandrine, Jeffrey C. H. Donovan, Flanagan, W. M., Milic, Andrea, Bhattacharya, Nandita, Slingerland, Joyce M.
Format Journal Article
LanguageEnglish
Published National Academy of Sciences of the United States of America 01.08.2000
Subjects
Biological Sciences
Breast cancer
Cell cycle
Cellular immunity
Cellular metabolism
Cyclins
Estrogen receptor modulators
Estrogens
Interphase
Oligonucleotides
Transfection
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Summary:Estrogens and antiestrogens influence the G1phase 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 G1cyclin-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.
ISSN:0027-8424
1091-6490