Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21.

Abstract

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 approximately 50% at 9-18 h. Similarly, cyclin E-associated kinase activity decreased by approximately 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.

• Authors: E A Musgrove, C S Lee, A L Cornish, A Swarbrick, R L Sutherland
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 11 Issue 1 Pg. 54-66 (Jan 1997) ISSN: 0888-8809 [Print] United States
• PMID: 8994188 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Estrenes
• Furans
• Hormone Antagonists
• Neoplasm Proteins
• Oncogene Proteins
• Progestins
• Recombinant Fusion Proteins
• Retinoblastoma Protein
• Org 31710
• Cyclin D1
• Mifepristone
• Cyclin-Dependent Kinases

Topics

• Breast Neoplasms (pathology)
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cyclin D1
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclin-Dependent Kinases (metabolism)
• Cyclins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Drug Resistance
• Estrenes (pharmacology)
• Furans (pharmacology)
• Hormone Antagonists (pharmacology)
• Humans
• Mifepristone (pharmacology)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Neoplasms, Hormone-Dependent (pathology)
• Oncogene Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Phosphorylation (drug effects)
• Progestins (antagonists & inhibitors)
• Protein Processing, Post-Translational (drug effects)
• Recombinant Fusion Proteins (metabolism)
• Retinoblastoma Protein (metabolism)
• Tumor Cells, Cultured