Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.
Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.
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发表时间：
2001-07
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通讯作者：
R. Bagatell;Omar Khan;G. Paine-Murrieta;C. Taylor;S. Akinaga;L. Whitesell
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作者：
R. Bagatell;Omar Khan;G. Paine-Murrieta;C. Taylor;S. Akinaga;L. Whitesell
类固醇激素受体已成为乳腺癌治疗的重要靶点。然而，尽管有良好的初始反应率，大多数肿瘤在开始治疗的一年内对目前的激素治疗变得难治。为了解决这个问题，我们评估了结合分子伴侣热休克蛋白90 （Hsp90）的药物对乳腺癌雌激素受体功能的影响。未受刺激的雌激素和孕激素受体以多分子复合物的形式存在，包括激素结合蛋白本身和一些必需的分子伴侣，包括Hsp90。我们发现hsp90结合药物格尔达霉素和根尖醇与伴侣蛋白的相互作用以一种不依赖配体的方式破坏了这些激素受体的稳定，导致体外培养的乳腺癌细胞中激素受体水平的深刻和长期的消耗。与这些发现一致的是，在体内给格尔达霉素衍生物17-烯丙基氨基格尔达霉素（17AAG; NSC330507）给雌激素补充的、携带肿瘤的SCID小鼠，导致子宫和肿瘤中黄体酮受体水平显著降低。药物管理也延迟了已建立的激素反应性MCF-7和T47D人类肿瘤异种移植物的生长，在治疗开始后长达3周。我们的结论是，鉴于其抗激素作用的新机制，在未来的临床试验中，应考虑检测17AAG和其他hsp90结合剂在难治性乳腺癌患者中的活性，无论是单独使用还是与常规激素拮抗剂联合使用。
Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer. Unstimulated estrogen and progesterone receptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90. We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of anti-hormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.