Cancer Biology Proteomics Group, Postgraduate Medical Institute of the University of Hull, Hull, UK.
J Proteomics. 2012 Feb 2;75(4):1276-83. doi: 10.1016/j.jprot.2011.11.005. Epub 2011 Nov 15.
Chemotherapy resistance is a major obstacle in effective neoadjuvant treatment for estrogen receptor-positive breast cancer. The ability to predict tumour response would allow chemotherapy administration to be directed towards only those patients who would benefit, thus maximising treatment efficiency. We aimed to identify putative protein biomarkers associated with chemotherapy resistance, using fresh tumour samples with antibody microarray analysis and then to perform pilot clinical validation experiments.
Chemotherapy resistant and chemotherapy sensitive tumour samples were collected from breast cancer patients who had received anthracycline based neoadjuvant therapy consisting of epirubicin with cyclophosphamide followed by docetaxel. A total of 5 comparative proteomics experiments were performed using invasive ductal carcinomas which demonstrated estrogen receptor positivity (luminal subtype). Protein expression was compared between chemotherapy resistant and chemotherapy sensitive tumour samples using the Panorama XPRESS Profiler725 antibody microarray containing 725 antibodies from a wide variety of cell signalling and apoptosis pathways. A pilot series of archival samples was used for clinical validation of putative predictive biomarkers.
AbMA analysis revealed 38 differentially expressed proteins which demonstrated at least 1.8 fold difference in expression in chemotherapy resistant tumours and 7 of these proteins (Zyxin, 14-3-3 theta/tau, tBID, Pinin, Bcl-xL, RIP and MyD88) were found in at least 2 experiments. Clinical validation in a pilot series of archival samples revealed 14-3-3 theta/tau and tBID to be significantly associated with chemotherapy resistance.
For the first time, antibody microarrays have been used to identify proteins associated with chemotherapy resistance using fresh breast cancer tissue. We propose a potential role for 14-3-3 theta/tau and tBID as predictive biomarkers of neoadjuvant chemotherapy resistance in breast cancer. Further validation in a larger sample series is now required.
化疗耐药是雌激素受体阳性乳腺癌有效新辅助治疗的主要障碍。预测肿瘤反应的能力将使化疗仅针对那些受益的患者进行，从而最大限度地提高治疗效率。我们旨在使用抗体微阵列分析从接受蒽环类药物新辅助治疗的乳腺癌患者中鉴定与化疗耐药相关的潜在蛋白质生物标志物，然后进行试点临床验证实验。
收集了接受表柔比星联合环磷酰胺序贯多西他赛的新辅助化疗的乳腺癌患者的化疗耐药和化疗敏感肿瘤样本。共进行了 5 项比较蛋白质组学实验，使用了显示雌激素受体阳性（腔型亚型）的浸润性导管癌。使用 Panorama XPRESS Profiler725 抗体微阵列（包含来自广泛的细胞信号和凋亡途径的 725 种抗体）比较化疗耐药和化疗敏感肿瘤样本之间的蛋白质表达。使用存档样本进行了初步验证实验，以验证潜在预测生物标志物的临床有效性。
AbMA 分析显示 38 种差异表达蛋白，在化疗耐药肿瘤中的表达至少增加了 1.8 倍，其中 7 种蛋白（Zyxyn、14-3-3θ/τ、tBID、Pinin、Bcl-xL、RIP 和 MyD88）在至少 2 项实验中发现。在初步验证实验中，存档样本发现 14-3-3θ/τ 和 tBID 与化疗耐药显著相关。
首次使用抗体微阵列在新鲜乳腺癌组织中鉴定与化疗耐药相关的蛋白质。我们提出 14-3-3θ/τ 和 tBID 作为乳腺癌新辅助化疗耐药的潜在预测生物标志物的作用。现在需要在更大的样本系列中进行进一步验证。
