Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer.
Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer.
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作者：
尽管他莫昔芬在临床上取得了成功，但其耐药性仍然是乳腺癌的主要挑战。在这里，我们表明Aurora-A通过调节雌激素受体（ER）α来决定他莫昔芬的敏感性。Aurora-A的异位表达减少，Aurora-A的缺失增强ERα阳性乳腺癌对他莫昔芬的敏感性。Aurora-A升高与ERα阳性肿瘤的复发显著相关。值得注意的是，Aurora-A抑制剂MLN 8237目前正在临床试验中，与他莫昔芬协同作用，克服了他莫昔芬耐药性。此外，Aurora-A与丝氨酸-167和-305上的ERα相互作用并使其磷酸化，导致ERα DNA结合和转录活性增加。Aurora-A水平升高与ERα阳性而非阴性乳腺癌的无病生存率显著相关。这些数据表明Aurora-A在他莫昔芬耐药中起关键作用，ERα是Aurora-A的真正底物。因此，Aurora-A代表ERα阳性肿瘤的预后标志物和他莫昔芬耐药乳腺癌的关键治疗靶点，Aurora-A抑制剂可用作他莫昔芬耐药肿瘤的独立或联合药物。
Despite the clinical success of tamoxifen, its resistance remains a major challenge in breast cancer. Here we show that Aurora-A determines tamoxifen sensitivity by regulation of estrogen receptor (ER)α. Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ERα-positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ERα-positive tumours. Notably, Aurora-A inhibitor MLN8237, which is currently in clinical trial, synergizes with tamoxifen and overcomes tamoxifen-resistance. Furthermore, Aurora-A interacts with and phosphorylates ERα on serine-167 and -305, leading to increase in ERα DNA-binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with disease-free survival in ERα-positive but not -negative breast cancers. These data suggest that Aurora-A plays a pivotal role in tamoxifen resistance and ERα is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a prognostic marker in ERα-positive tumor and a critical therapeutic target in tamoxifen-resistant breast cancer, and Aurora-A inhibitor could be used as either an independent or concurrent agent in tamoxifen-resistant tumour.
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影响因子：
8
作者：
通讯作者：
--
DOI：
10.2165/00129785-200404010-00003
发表时间：
2004-01-01
期刊：
American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
影响因子：
--
作者：
Barkhem, Tomas;Nilsson, Stefan;Gustafsson, Jan-Ake
通讯作者：
Gustafsson, Jan-Ake
影响因子：
4.3
作者：
Holz, Marina K.
通讯作者：
Holz, Marina K.
影响因子：
4.8
作者：
Li, QY;Kaneko, S;Cheng, JQ
通讯作者：
Cheng, JQ
影响因子：
5.3
作者：
Lim, Kian-Huat;Brady, Donita C.;Counter, Christopher M.
通讯作者：
Counter, Christopher M.