Table_4_BJ-B11, an Hsp90 Inhibitor, Constrains the Proliferation and Invasion of Breast Cancer Cells.DOCX

Breast cancer is the leading cause of cancer-related deaths in women; however, its underlying etiology remains largely unknown. In this study, we systematically analyzed breast cancer tissues using comprehensive iTRAQ labeled quantitative proteomics, identifying 841 differentially expressed proteins (474 and 367 significantly over- and under-expressed, respectively), which were annotated by protein domain analysis. All the heat shock proteins identified were upregulated in breast cancer tissues; Hsp90 upregulation was also validated by RT-qPCR and immunohistochemistry, and high Hsp90 protein levels correlated with poorer survival. Hsp90AA1 overexpression promoted MDA-MB-231 cell proliferation, whilst BJ-B11, an Hsp90 inhibitor, hampered their invasion, migration, and proliferation in a time and dose-dependent manner and induced cell cycle arrest and apoptosis. BJ-B11 inhibited the expression of epithelial-mesenchymal transition (EMT) marker in MDA-MB-231 cells, whereas Hsp90AA1 promoted its expression. Moreover, BJ-B11 inhibited tumor growth in xenograft model. Altogether, Hsp90 activation is a risk factor in breast cancer patients, and BJ-B11 could be used to treat breast cancer.

乳腺癌是导致女性癌症相关死亡的首要病因，但其潜在发病机制迄今仍未完全明确。本研究采用全范围同位素标记相对和绝对定量（iTRAQ）标记定量蛋白质组学技术对乳腺癌组织进行系统分析，共鉴定出841个差异表达蛋白（其中显著高表达与低表达蛋白分别为474个和367个），并通过蛋白质结构域分析完成了相关注释。本研究鉴定得到的所有热休克蛋白（heat shock proteins, HSPs）在乳腺癌组织中均呈上调表达；热休克蛋白90（Hsp90）的上调现象同时通过逆转录定量聚合酶链反应（RT-qPCR）与免疫组织化学（immunohistochemistry）得到验证，且高表达的Hsp90蛋白与乳腺癌患者的不良预后显著相关。热休克蛋白90α1（Hsp90AA1）过表达可促进MDA-MB-231细胞的增殖；而Hsp90抑制剂BJ-B11则以时间和剂量依赖的方式抑制该细胞的侵袭、迁移与增殖，并诱导细胞周期阻滞与细胞凋亡。BJ-B11可下调MDA-MB-231细胞的上皮间质转化（EMT）标志物表达，而Hsp90AA1则可上调该类标志物的表达。此外，BJ-B11可在异种移植瘤模型中抑制肿瘤生长。综上，Hsp90激活是乳腺癌患者的不良风险因素，BJ-B11可用于乳腺癌的治疗。