Potentiation of ICI182,780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790.
ICI182,780 (Fulvestrant) is a pure anti-estrogen used in adjuvant therapies of breast cancer. This compound not only inhibits the transcriptional activities of the estrogen receptor-alpha (ER alpha) but also induces its proteasome-dependent degradation. The latter activity is believed to be required for the antiproliferative effects of ICI182,780. Estrogen receptor-related receptor-alpha (ERR alpha) is an orphan member of the nuclear receptor superfamily that is expressed in a wide range of tissues including breast tumors, in which its high expression correlates with poor prognosis. Although not regulated by any natural ligand, ERR alpha can be deactivated by the synthetic molecule XCT790. Here we demonstrate that this compound also induces a proteasome degradation of ERR alpha. We also show that although it does not act directly on the steady-state level of ER alpha, XCT790 potentiates the ICI182,780-induced ER alpha degradation. We suggest that treatment with XCT790 could thus enhance the efficacy of ICI182,780 in ER alpha-dependent pathologies such as breast cancer.
Lanvin
Olivia
O
Institut de Génomique Fontionnelle, Université de Lyon, F-69003 Lyon, France; Institut National de la Recherche Agronomique (INRA), CNRS, Université Lyon 1, Ecole Normale Supérieure, F-69364 Lyon, France.
Bianco
Stéphanie
S
Institut de Génomique Fontionnelle, Université de Lyon, F-69003 Lyon, France; Institut National de la Recherche Agronomique (INRA), CNRS, Université Lyon 1, Ecole Normale Supérieure, F-69364 Lyon, France.
Kersual
Nathalie
N
INSERM U826, F-34298 Montpellier, France.
Chalbos
Dany
D
INSERM U826, F-34298 Montpellier, France.
Vanacker
Jean-Marc
JM
Institut de Génomique Fontionnelle, Université de Lyon, F-69003 Lyon, France; Institut National de la Recherche Agronomique (INRA), CNRS, Université Lyon 1, Ecole Normale Supérieure, F-69364 Lyon, France. Electronic address: jean-marc.vanacker@ens-lyon.fr.
D018931:Antineoplastic Agents, Hormonal / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004958:Estradiol / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000819:agonists; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009570:Nitriles / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000819:agonists; D013844:Thiazoles / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000097983:ERRalpha Estrogen-Related Receptor
D018931:Antineoplastic Agents, Hormonal; D004958:Estradiol; D047628:Estrogen Receptor alpha; D000077267:Fulvestrant; D009570:Nitriles; D046988:Proteasome Endopeptidase Complex; D011960:Receptors, Estrogen; D013844:Thiazoles; D000097983:ERRalpha Estrogen-Related Receptor; C488234:XCT790