Stimulation of human breast cancer MCF-7 cells with estrogen prevents cell cycle arrest by HMG-CoA reductase inhibitors.
Inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, such as Simvastatin and Lovastatin, reduce the rate of DNA synthesis and proliferation of a wide variety of cell types in vitro, by inducing a cell cycle arrest in G1. In estrogen-free medium, DNA synthesis is reduced by more that 90% following exposure of normal and transformed human breast epithelia] cells to 20 microM Simvastatin or Lovastatin for 24 to 42 hrs. We show here that stimulation of estrogen responsive MCF-7 cells with nanomolar concentrations of 17beta-estradiol (E2) prevents inhibition of DNA synthesis by these compounds. The effect of the hormone is antagonized by both steroidal and non steroidal antiestrogens, and it is not detectable in estrogen receptor-negative MCF-10a cells. Cell cycle analysis demonstrates that HMG-CoA reductase inhibitors are unable to induce G1 arrest of MCF-7 cells in the presence of E2.
Addeo
R
R
Instituto di Patologia generale e Oncologia, Seconda Università di Napoli, Italy.
Altucci
L
L
Battista
T
T
Bonapace
I M
IM
Cancemi
M
M
Cicatiello
L
L
Germano
D
D
Pacilio
C
C
Salzano
S
S
Bresciani
F
F
Weisz
A
A
D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D045166:Estradiol Congeners / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D019821:Simvastatin; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D004815:Epidermal Growth Factor; D008148:Lovastatin; D019821:Simvastatin