Osborne C Kent, Bardou Valerie, Hopp Torsten A, Chamness Gary C, Hilsenbeck Susan G, Fuqua Suzanne A W, Wong Jiemin, Allred D Craig, Clark Gary M, Schiff Rachel
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
J Natl Cancer Inst. 2003 Mar 5;95(5):353-61. doi: 10.1093/jnci/95.5.353.
AIB1 (SRC-3) is an estrogen receptor (ER) coactivator that, when overexpressed in cultured cells, can reduce the antagonist activity of tamoxifen-bound 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.
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.
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).
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.
AIB1（SRC-3）是一种雌激素受体（ER）共激活因子，在培养细胞中过表达时，可降低与他莫昔芬结合的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AIB1。为了确定单独的高AIB1表达或与HER-2共同表达是否会降低他莫昔芬对乳腺癌患者的疗效，我们对长期临床随访的乳腺癌患者肿瘤中AIB1和HER-2的表达进行了定量分析，这些患者在乳腺癌手术后未接受辅助治疗或接受辅助他莫昔芬治疗。
采用蛋白质印迹分析测定316例乳腺癌患者肿瘤中AIB1和HER-2蛋白水平。使用Spearman等级相关性评估分子变量（例如，AIB1、ER、孕激素受体、p53、Bcl-2的表达）、肿瘤特征和患者预后。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。使用Cox比例风险模型通过多变量分析评估调整其他预后因素后AIB1对DFS的影响。所有统计检验均为双侧检验。
未接受辅助他莫昔芬治疗的患者中，高AIB1表达与较好的预后和较长的DFS相关（P = 0.018，对数秩检验）。相比之下，接受他莫昔芬治疗的患者中，高AIB1表达与较差的DFS相关（P = 0.049，对数秩检验），这表明存在他莫昔芬耐药性。AIB1表达与他莫昔芬治疗之间的相互作用检验具有统计学意义（P = 0.004）。当同时考虑AIB1和HER-2的表达时，肿瘤同时高表达AIB1和HER-2的患者接受他莫昔芬治疗的预后比所有其他患者加起来更差（P = 0.002，对数秩检验）。
他莫昔芬对乳腺癌患者的抗肿瘤活性可能部分取决于肿瘤中AIB1和HER-2的水平。因此，AIB1可能是一个重要的诊断和治疗靶点。
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