Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer
Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer
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DOI：
10.1093/jnci/95.5.353
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发表时间：
2003-03-05
期刊：
影响因子：
--
通讯作者：
Schiff, R
中科院分区：
文献类型：
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作者：
Osborne, CK;Bardou, V;Schiff, R
背景资料：AIB1（SRC-3）是一种雌激素受体（ER）辅激活剂，当在培养的细胞中过表达时，可以降低他莫昔芬-猎犬ER的拮抗剂活性。通过HER-2受体途径的信号传导通过磷酸化激活AIB 1。为了确定AIB1单独或与HER-2一起高表达是否会降低他莫昔芬在乳腺癌患者中的有效性，我们定量了乳腺癌患者肿瘤中AIB1和HER-2的表达，这些患者在乳腺癌手术后接受了无辅助治疗或辅助他莫昔芬治疗，并进行了长期临床随访。方法：采用免疫印迹法检测316例乳腺癌组织中AIB 1和HER-2蛋白的表达。分子变量（例如，AIB 1、ER、孕激素受体、p53、Bcl-2的表达）、肿瘤特征和患者预后采用斯皮尔曼等级相关进行评估。无病生存期（DFS）曲线来自Kaplan-Meier估计值，并通过对数秩检验比较曲线。采用考克斯比例风险模型，通过多变量分析评估AIB 1对DFS的影响（根据其他预后因素调整）。所有统计检验均为双侧检验。结果如下：未接受他莫昔芬辅助治疗的患者中AIB1高表达与更好的预后和更长的DFS相关（P = 0.018，对数秩检验）。相反，对于接受他莫昔芬治疗的患者，AIB1高表达与DFS恶化相关（P = 0.049，对数秩检验），这表明他莫昔芬耐药。AIB1表达和他莫昔芬治疗之间相互作用的检验具有统计学显著性（P =.004）。当同时考虑AIB1和HER-2的表达时，肿瘤同时表达高水平AIB1和HER-2的患者接受他莫昔芬治疗的结局比所有其他患者联合治疗的结局更差（P = 0.002，对数秩检验）。结论：他莫昔芬对乳腺癌患者的抗肿瘤活性可能部分取决于AIB 1和HER-2的肿瘤水平。因此，AIB1可能是一个重要的诊断和治疗靶点。
Background: AIB1 (SRC-3) is an estrogen receptor (ER) coactivator that, when overexpressed in cultured cells, can reduce the antagonist activity of tamoxifen-hound ERs. Signaling through the HER-2 receptor pathway activates AIB1 by phosphorylation. To determine whether high AIB1 expression alone or together with HER-2 reduces the effectiveness of tamoxifen in breast cancer patients, we quantified expression of AIB1 and HER-2 in tumors from breast cancer patients with long-term clinical follow-up who received either no adjuvant therapy or adjuvant tamoxifen therapy after breast cancer surgery. Methods: AIB1 and HER-2 protein levels in tumors from 316 breast cancer patients were determined using western blot analysis. Molecular variables (e.g., expression of AIB1, ER, progesterone receptor, p53, Bcl-2), tumor characteristics, and patient outcome were assessed using Spearman rank correlation. Disease-free survival (DFS) curves were derived from Kaplan-Meier estimates, and the curves were compared by log-rank tests. The effect of AIB1 on DFS adjusted for other prognostic factors was assessed by multivariable analysis using the Cox proportional hazards model. All statistical tests were two-sided. Results: High AIB1 expression in patients not receiving adjuvant tamoxifen therapy was associated with better prognosis and longer DFS (P =.018, log-rank test). In contrast, for patients who did receive tamoxifen therapy, high AIB1 expression was associated with worse DFS (P =.049, log-rank test), which is indicative of tamoxifen resistance. The test for interaction between AIB1 expression and tamoxifen therapy was statistically significant (P =.004). When expression of AIB1 and HER-2 were considered together, patients whose tumors expressed high levels of both AIB1 and HER-2 had worse outcomes with tamoxifen therapy than all other patients combined (P =.002, log-rank test). Conclusions: The antitumor activity of tamoxifen in patients with breast cancer may be determined, in part, by tumor levels of AIB1 and HER-2. Thus, AIB1 may be an important diagnostic and therapeutic target.