The AF-2 region of the retinoic acid receptor alpha mediates retinoic acid inhibition of estrogen receptor function in breast cancer cells.
The growth of estrogen receptor (ER)-positive breast cancer cells is inhibited by all-trans-retinoic acid (RA). In the present study, estrogen (E2) induction of pS2 mRNA levels was significantly reduced within 6 h following cotreatment with RA. In transient transfection experiments, RA repressed transactivation from a vitellogenin E2-responsive element by approximately 50% and wild-type RA receptor alpha (RARalpha) or RARbeta enhanced this inhibition. Transfection of truncated RARalpha mutants terminating before or at amino acid 412 markedly decreased RA inhibition of E2-induced reporter gene activity. Expression of RARs with deletions of amino acids 413 and 414 in the transactivation-2 (AF-2) domain also reduced RA inhibition, while deletions and point mutations beyond amino acid 414 behaved like the wild-type RARalpha. RA-treated MCF-7 cells transfected with an RARalpha AF-2 region mutant were twice as sensitive to growth inhibition as untransfected and vector-transfected control cells. Thus, the AF-2 domain in the C terminus of the RARalpha mediates RA inhibition of ER-induced transcription in breast cancer cells. In addition, transcriptional interference between RARs and ERs may contribute to RA inhibition of ER-positive breast cancer cell growth.
Pratt
M A
MA
Department of Pharmacology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Deonarine
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D
Teixeira
C
C
Novosad
D
D
Tate
B F
BF
Grippo
J F
JF
D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011506:Proteins; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors*; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D000072482:Retinoic Acid Receptor alpha; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D000071163:Trefoil Factor-1; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D017931:DNA Primers; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D011506:Proteins; C000607071:RARA protein, human; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D014212:Tretinoin