Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21.
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.
Musgrove
E A
EA
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
Lee
C S
CS
Cornish
A L
AL
Swarbrick
A
A
Sutherland
R L
RL
D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D004351:Drug Resistance; D004963:Estrenes / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011372:Progestins / Q000037:antagonists & inhibitors*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004963:Estrenes; D005663:Furans; D006727:Hormone Antagonists; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011372:Progestins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; C076196:Org 31710; D019938:Cyclin D1; D015735:Mifepristone; D018844:Cyclin-Dependent Kinases