Pick Elah, Kluger Yuval, Giltnane Jennifer M, Moeder Christopher, Camp Robert L, Rimm David L, Kluger Harriet M
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Cancer Res. 2007 Apr 1;67(7):2932-7. doi: 10.1158/0008-5472.CAN-06-4511.
The heat shock protein HSP90 chaperones proteins implicated in breast cancer progression, including Her2/neu. HSP90-targeting agents are in clinical trials for breast cancer. HSP90 expression is high in breast cancer cell lines, yet no large studies have been conducted on expression in human tumors and the association with clinical/pathologic variables. Tissue microarrays containing 10 cell lines and primary specimens from 655 patients with 10-year follow-up were assessed using our automated quantitative analysis (AQUA) method; we used cytokeratin to define pixels as breast cancer (tumor mask) within the array spot and measured HSP90 expression within the mask using Cy5-conjugated antibodies. We similarly assessed estrogen receptor, progesterone receptor, and Her2/neu expression. HSP90 expression was more variable in human tumors than in cell lines (P < 0.0001). High HSP90 expression was associated with decreased survival (P = 0.0024). On multivariable analysis, high HSP90 expression remained an independent prognostic marker. High HSP90 expression was associated with high Her2/neu and estrogen receptor, large tumors, high nuclear grade, and lymph node involvement. Although HSP90 levels were high in all our cell lines, expression in tumors was more variable. High HSP90 expression in primary breast cancer defines a population of patients with decreased survival. Evaluation of HSP90 expression in early-stage breast cancer may identify a subset of patients requiring more aggressive or pathway-targeted treatment. Prospective studies are needed to confirm the prognostic role of HSP90, as well as the predictive role of HSP90 expression in patients treated with HSP90 inhibitors.
热休克蛋白HSP90可对包括Her2/neu在内的、与乳腺癌进展相关的蛋白进行分子伴侣介导的折叠。靶向HSP90的药物正在进行乳腺癌的临床试验。HSP90在乳腺癌细胞系中高表达，但尚未针对人类肿瘤中的表达及其与临床/病理变量的关联进行大规模研究。我们使用自动定量分析（AQUA）方法评估了包含10种细胞系和来自655例患者的原发标本且有10年随访数据的组织芯片；我们使用细胞角蛋白将阵列点内的像素定义为乳腺癌（肿瘤掩码），并使用Cy5偶联抗体测量掩码内的HSP90表达。我们同样评估了雌激素受体、孕激素受体和Her2/neu的表达。HSP90在人类肿瘤中的表达比在细胞系中更具变异性（P < 0.0001）。HSP90高表达与生存率降低相关（P = 0.0024）。在多变量分析中，HSP90高表达仍然是一个独立的预后标志物。HSP90高表达与高Her2/neu和雌激素受体、大肿瘤、高核分级以及淋巴结受累相关。尽管我们所有的细胞系中HSP90水平都很高，但肿瘤中的表达更具变异性。原发性乳腺癌中HSP90高表达定义了一组生存率降低的患者群体。评估早期乳腺癌中HSP90的表达可能会识别出需要更积极或靶向通路治疗的患者亚组。需要进行前瞻性研究以确认HSP90的预后作用以及HSP90表达在接受HSP90抑制剂治疗患者中的预测作用。
