Potentiation of ICI182,780 (fulvestrant)-induced estrogen receptor-α degradation by the estrogen receptor-related receptor-α inverse agonist XCT790
Potentiation of ICI182,780 (fulvestrant)-induced estrogen receptor-α degradation by the estrogen receptor-related receptor-α inverse agonist XCT790
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DOI：
10.1074/jbc.m704295200
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发表时间：
2007-09-28
影响因子：
4.8
通讯作者：
Vanacker, Jean-Marc
中科院分区：
文献类型：
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作者：
Lanvin, Olivia;Bianco, Stephanie;Vanacker, Jean-Marc
ICI182,780(Fulvestrant)是一种用于乳腺癌辅助治疗的纯抗雌激素。该化合物不仅抑制雌激素受体α(ERα)的转录活性，而且诱导其蛋白酶体依赖的降解。后一种活性被认为是ICI182,780抗增殖作用所必需的。雌激素受体相关受体-α(ERR-α)是核受体超家族中的孤儿成员，广泛表达于包括乳腺肿瘤在内的多种组织中，其高表达与预后不良相关。虽然ERRα不受任何天然配体的调节，但它可以被合成分子XCT790灭活。在这里，我们证明，该化合物还诱导蛋白酶体降解的ERRα。我们还表明，尽管XCT790不直接作用于ERα的稳态水平，但它增强了ICI182,780诱导的ERα的降解。我们认为，XCT790的治疗可以因此提高ICI182,780在乳腺癌等ERα依赖的病理中的疗效。
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.