Kirkegaard Tove, McGlynn Liane M, Campbell Fiona M, Müller Sven, Tovey Sian M, Dunne Barbara, Nielsen Kirsten V, Cooke Timothy G, Bartlett John M S
Endocrine Cancer Group, Section of Surgical and Translational Research, Glasgow University, Glasgow Royal Infirmary, Glasgow, United Kingdom.
Clin Cancer Res. 2007 Mar 1;13(5):1405-11. doi: 10.1158/1078-0432.CCR-06-1933.
Amplified in breast cancer 1 (AIB1) is a member of the p160/steroid receptor coactivators family and is involved in estrogen-dependent gene transcription by reducing the antagonistic activity of tamoxifen-bound estrogen receptor-alpha (ER-alpha). The present study was carried out to test the hypothesis that AIB1 protein expression and/or gene amplification mediates tamoxifen resistance in breast cancer.
Immunohistochemistry using AIB1 antibody and fluorescence in situ hybridization using probes specific for AIB1 and chromosome 20 was done on 402 ER-alpha-positive tamoxifen-treated breast cancers.
AIB1 overexpression was not associated with relapse during treatment with tamoxifen. In contrast, high AIB1 expression in patients with human epidermal growth factor receptor (HER) 2- and HER3-overexpressing tumors or tumors expressing one or more of HER1, HER2, or HER3 (HER1-3 positive) was associated with an increased risk of relapse on tamoxifen [hazard ratio, 2.20; 95% confidence interval, 1.07-3.52 (P = 0.0416); hazard ratio, 2.42; 95% confidence interval, 1.32-4.43 (P = 0.0030), respectively]. AIB1 gene amplification was observed in 18 of 362 (5%) patients. High AIB1 gene copy number had no effect on overall or disease-free survival.
Data presented here support a role for AIB1 expression on relapse during tamoxifen treatment in hormone-responsive HER-expressing clinical breast cancers and support clinical evidence, suggesting a cross-talk between ER-alpha and growth factor receptor pathways through changes in expression of specific coactivator proteins, such as AIB1. This study highlights the potential that tumor profiling, using multiple markers of treatment response, may improve patient selection for endocrine treatment, such as tamoxifen or aromatase inhibitors.
乳腺癌中扩增基因1（AIB1）是p160/类固醇受体共激活因子家族的成员，通过降低与他莫昔芬结合的雌激素受体α（ER-α）的拮抗活性参与雌激素依赖性基因转录。本研究旨在验证AIB1蛋白表达和/或基因扩增介导乳腺癌对他莫昔芬耐药这一假说。
对402例接受他莫昔芬治疗的ER-α阳性乳腺癌进行AIB1抗体免疫组化以及使用AIB1和20号染色体特异性探针的荧光原位杂交。
AIB1过表达与他莫昔芬治疗期间的复发无关。相反，在人表皮生长因子受体（HER）2和HER3过表达肿瘤患者或表达HER1、HER2或HER3中一种或多种（HER1-3阳性）的肿瘤患者中，高AIB1表达与他莫昔芬治疗后复发风险增加相关[风险比分别为2.20；95%置信区间为1.07 - 3.52（P = 0.0416）；风险比为2.42；95%置信区间为1.32 - 4.43（P = 0.0030）]。在362例患者中的18例（5%）观察到AIB1基因扩增。高AIB1基因拷贝数对总生存期或无病生存期无影响。
此处呈现的数据支持AIB1表达在激素反应性HER表达的临床乳腺癌他莫昔芬治疗期间复发中的作用，并支持临床证据，提示通过特定共激活蛋白如AIB1表达的变化，ER-α与生长因子受体途径之间存在相互作用。本研究强调了使用多种治疗反应标志物进行肿瘤分析可能改善内分泌治疗（如他莫昔芬或芳香化酶抑制剂）患者选择的潜力。
