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

Mol Endocrinol. 1997 Jan;11(1):54-66. doi: 10.1210/mend.11.1.9869.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Cyclins / biosynthesis*
  • Cyclins / genetics
  • Cyclins / physiology
  • Drug Resistance
  • Estrenes / pharmacology*
  • Furans / pharmacology*
  • Hormone Antagonists / pharmacology*
  • Humans
  • Mifepristone / pharmacology*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology
  • Neoplasms, Hormone-Dependent / pathology*
  • Oncogene Proteins / antagonists & inhibitors*
  • Oncogene Proteins / biosynthesis
  • Oncogene Proteins / genetics
  • Phosphorylation / drug effects
  • Progestins / antagonists & inhibitors*
  • Protein Processing, Post-Translational / drug effects*
  • Recombinant Fusion Proteins / metabolism
  • Retinoblastoma Protein / metabolism
  • Tumor Cells, Cultured

Substances

  • 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