The tamoxifen-responsive estrogen receptor alpha mutant D351Y shows reduced tamoxifen-dependent interaction with corepressor complexes.
The effects of estrogen and anti-estrogen are mediated through the estrogen receptors ERalpha and beta, which function as ligand-induced transcriptional factors. The nonsteroidal anti-estrogen tamoxifen is the most commonly used endocrine in the treatment of all stages of breast cancer in both pre- and postmenopausal women. Several lines of evidence have indicated that tamoxifen promotes association between ERalpha and corepressors N-CoR or silencing mediator for retinoid and thyroid hormone receptor (SMRT). Our results indicate that N-CoR/SMRT recognize and interact with helices H3 and H5 of the ERalpha ligand-binding domain in a 4-hydroxy tamoxifen-dependent manner. The mutant ERalpha(D351Y), derived from a tamoxifen-stimulated tumor and containing an amino acid substitution at position 351 within H3, showed reduced interaction with N-CoR/SMRT and high tamoxifen-induced activation function-1 (AF-1) activity. While the estradiol-dependent transcriptional activity of ERalpha(D351Y) was almost equal to that of wild-type ERalpha, the mutant exhibited higher levels of transcriptional activity in the presence of both E2 and 4-hydroxy tamoxifen compared with wild-type ERalpha. These results may explain the observation that the growth of tumor cells expressing ERalpha(D351Y) can be stimulated by tamoxifen, E2, or both.
Yamamoto
Y
Y
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0034, Japan.
Wada
O
O
Suzawa
M
M
Yogiashi
Y
Y
Yano
T
T
Kato
S
S
Yanagisawa
J
J
D000595:Amino Acid Sequence; D002460:Cell Line; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005982:Glutathione Transferase / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000737:chemistry*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D008024:Ligands; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D008156:Luciferases; D005982:Glutathione Transferase; D006655:Histone Deacetylases