Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer
Elevated expression of CUEDC2 protein confers endocrine resistance in breast cancer
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DOI：
10.1038/nm.2369
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发表时间：
2011-06-01
期刊：
影响因子：
82.9
通讯作者：
Zhang, Xue-Min
中科院分区：
文献类型：
--
作者：
Pan, Xin;Zhou, Tao;Zhang, Xue-Min
内分泌抵抗是乳腺癌激素治疗的主要障碍。虽然雌激素受体-α（ER-α）的表达减少是内分泌抵抗的已知促成因素，但ER-α下调内分泌抵抗的机制仍不完全清楚。在这里，我们报告说，CUE结构域蛋白-2（CUEDC 2），一个泛素结合基序含有蛋白质，是乳腺癌内分泌抵抗的一个关键因素。我们发现CUEDC 2通过泛素-蛋白酶体途径调节ER-α蛋白的稳定性。通过对来自一个大型乳腺癌受试者队列的样本的研究，我们发现CUEDC 2和ER-α蛋白表达之间存在很强的负相关性。值得注意的是，具有高度表达CUEDC 2的肿瘤的受试者对他莫昔芬治疗的反应性差，并且复发的可能性高。我们进一步表明，异位CUEDC 2表达损害乳腺癌细胞对他莫昔芬的反应性。因此，我们的研究结果表明，CUEDC 2是乳腺癌对内分泌治疗耐药的关键决定因素。
Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-alpha (ER-alpha) is a known contributing factor to endocrine resistance, the mechanism of ER-alpha downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-alpha protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-alpha protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.