Antiestrogenic effects of all-trans-retinoic acid and 1,25-dihydroxyvitamin D3 in breast cancer cells occur at the estrogen response element level but through different molecular mechanisms.
Most breast tumors show estrogen-dependent growth and are thus susceptible to antiestrogenic therapy. MCF-7 cells, obtained from a human estrogen-dependent breast carcinoma, are widely used for studying the modulation of estrogenic responses by different effectors. All-trans-retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (Vit D3) inhibited estrogen-induced growth of MCF-7 cells and their effect was potentiated by the classical antiestrogen, hydroxytamoxifen. In MCF-7 cells, we found that RA and Vit D3 also inhibited estrogen-induced transcription; this was shown both for an endogenous gene (pS2) and for various exogenous transfected genes. Their inhibitory effect could not be reversed by increasing estradiol concentrations, showing that contrary to classical antiestrogens, they did not compete with estradiol to bind the estrogen receptor (ER). Analysis of the inhibitory mechanisms indicates that RA and Vit D3 receptors can directly or indirectly impair the binding of ER to the estrogen responsive element. The antagonist effect of RA would be found especially at DNA level since it seems to essentially involve an estrogen responsive element. The antagonist effect of Vit D3 would be found especially at the ER level since it seems to concern estrogen binding and dimerization domains of ER. We conclude that the antiestrogenic effects of RA and Vit D3 are similar since they can, via their receptors, interfere with estrogenic action at the estrogen responsive element level but that they are not identical since different molecular mechanisms are involved.
Demirpence
E
E
INSERM U 58, Montpellier, France.
Balaguer
P
P
Trousse
F
F
Nicolas
J C
JC
Pons
M
M
Gagne
D
D
D001943:Breast Neoplasms / Q000188:drug therapy*; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002678:Chimera / Q000187:drug effects / Q000235:genetics; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics; D011506:Proteins; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D018003:Receptors, Calcitonin / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000071163:Trefoil Factor-1; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D004965:Estrogen Antagonists; D004967:Estrogens; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D018003:Receptors, Calcitonin; D018168:Receptors, Retinoic Acid; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D014212:Tretinoin; D002117:Calcitriol