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Antiprogestin Inhibition of Cell Cycle Progression in T-47D Breast Cancer Cells Is Accompanied by Induction of the Cyclin-Dependent Kinase Inhibitor p21

Cancer Research Program Garvan Institute of Medical Research St. Vincent’s Hospital Sydney, New South Wales 2010, Australia

Progestin antagonists inhibit the proliferation of progesterone receptor-positive cells, including breast cancer cells, by G₁ phase-specific actions, but the molecular targets involved are not defined. Reduced phosphorylation of pRB, a substrate for G₁ cyclin-dependent kinases (CDKs) in vivo, was apparent after 9 h treatment of T-47D breast cancer cells with the antiprogestins RU 486 or ORG 31710, accompanying changes in S phase fraction. Although the abundance of cyclin D1, Cdk4, and Cdk6 did not decrease, cyclin D1-associated kinase activity was reduced by 50% at 9–18 h. Similarly, cyclin E-associated kinase activity decreased by 60% at 12–24 h in the absence of significant changes in the abundance of cyclin E and Cdk2. The CDK inhibitor p21 increased in mRNA and protein abundance and was present at increased levels in cyclin D1 and cyclin E complexes at times when their kinase activity was decreased. Increased p21 protein abundance was observed in another antiprogestin-sensitive cell line, BT 474, but not in two breast cancer cell lines insensitive to antiprogestins. These data suggest increased p21 abundance and concurrent inhibition of CDK activity as a mechanism for antiprogestin induction of growth arrest. Antiprogestin effects on proliferation were markedly reduced after ectopic expression of cyclin D1, indicating that inhibition of cyclin D1 function is a critical element in antiprogestin inhibition of proliferation. However, these data also implicate regulation of cyclin E function in antiprogestin regulation of cell cycle progression.

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