Full activation of estrogen receptor alpha activation function-1 induces proliferation of breast cancer cells.
The effects of estrogen and anti-estrogen are mediated through the estrogen receptors (ER) alpha and beta, which function as ligand-induced transcriptional factors. Recently, one of the phthalate esters, n-butylbenzyl phthalate (BBP), has been shown to induce estrogen receptor-mediated responses. By using the truncated types of ER mutants, we revealed that activation function-1 (AF-1) activity was necessary for the BBP-dependent transactivation function of ERalpha. AF-1 is also known to be responsible for the partial agonistic activity of tamoxifen. Whereas tamoxifen exhibits an anti-estrogenic effect on proliferation of the MCF-7 breast cancer cell line, BBP showed an estrogenic effect on MCF-7 to stimulate proliferation. In vivo and in vitro binding assays revealed that whereas 4-hydroxytamoxifen (OHT) induced binding of ERalpha to both an AF-1 coactivator complex (p68/p72 and p300) and corepressor complexes (N-CoR/SMRT), BBP selectively enhanced the binding to the AF-1 coactivators. We also showed that the transcriptional activity of OHT-bound ERalpha was modulated by the ratio between the AF-1 coactivator and corepressor complexes. Expression of a dominant-negative type of N-CoR inhibited the interaction between OHT-bound ERalpha and N-CoR/SMRT and enhanced the transcriptional activity of OHT-bound ERalpha. Furthermore, the cell growth of MCF-7 stably expressing the dominant-negative type of N-CoR was enhanced by the addition of OHT. These results indicated that fully activated AF-1 induces the stimulation of breast cancer growth and that the ratio between AF-1 coactivators and corepressors plays a key role to prevent proliferation of tumor by tamoxifen.
Fujita
Tetsuo
T
Institute of Applied Biochemistry, University of Tsukuba, 1-1-1 Tenno-dai, Tsukuba Science City, Ibaraki 305-8572, Japan.
Kobayashi
Yoko
Y
Wada
Osamu
O
Tateishi
Yukiyo
Y
Kitada
Lina
L
Yamamoto
Yasuji
Y
Takashima
Hisashige
H
Murayama
Akiko
A
Yano
Tetsu
T
Baba
Tadashi
T
Kato
Shigeaki
S
Kawabe
Yoh-Ichi
Y
Yanagisawa
Junn
J
D016475:3T3 Cells; D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010795:Phthalic Acids / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
D047628:Estrogen Receptor alpha; C086185:IFNGR2 protein, human; C490116:Ifngr2 protein, mouse; D010795:Phthalic Acids; D011960:Receptors, Estrogen; D017471:Receptors, Interferon; D012097:Repressor Proteins; D013629:Tamoxifen; C016601:afimoxifene; C027561:butylbenzyl phthalate