The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer
The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer
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内质网应激标记物 GRP78 和 CHOP 预测乳腺癌的无病生存率和化疗反应
DOI：
10.1007/s10549-014-2967-x
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发表时间：
2014-06-01
影响因子：
3.8
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
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作者：
Zheng, Yi-Zi;Cao, Zhi-Gang;Shao, Zhi-Ming
葡萄糖调节蛋白（GRP）78和C/-EBP同源蛋白（CHOP）通常用作内质网（ER）应激的标志物。GRP 78作为一种ER分子伴侣，是一种有效的抗凋亡因子，并赋予耐药性，而CHOP是ER应激相关细胞死亡的关键起始因子。我们的目的是调查GRP 78和CHOP在接受辅助化疗的乳腺癌患者中的预测价值。使用包含来自复旦大学上海肿瘤中心诊断为浸润性导管乳腺癌的女性患者的250个肿瘤的组织芯片进行GRP 78和CHOP的免疫组织化学筛查。染色结果进行半定量评分，并构建预测模型来验证假设。在这项回顾性队列研究中，CHOP与无病生存期延长相关（HR = 0.385，95% CI 0.215-0.688;P= 0.001），而GRP 78显示出相反的相关性（HR = 4.573; 95% CI 2.291-9.128;P< 0.001）。此外，在GRP 78阳性亚组中，CHOP过表达与较低的复发风险相关。在受试者工作特征分析中，结合上述两个标志物的预测模型的预测能力优于传统模型（曲线下面积比较P= 0.0085）。在蒽环类药物治疗的亚组中，GRP 78和CHOP的联合表现出相似的预测意义。累积起来，我们的研究结果表明ER应激标志物与乳腺癌患者的临床结局之间存在密切联系。
Glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) are commonly used as markers of endoplasmic reticulum (ER) stress. As an ER chaperone, GRP78 functions as a potent anti-apoptotic factor and confers drug resistance, whereas CHOP is a key initiating factor of ER stress-related cell death. We aimed at investigating the predictive values of GRP78 and CHOP in breast cancer patients who underwent adjuvant chemotherapy. An immunohistochemistry screen for GRP78 and CHOP was performed using a tissue microarray containing 250 tumors from female patients diagnosed with invasive ductal breast carcinoma at the Fudan University Shanghai Cancer Center. The staining results were scored semi-quantitatively, and a prediction model was constructed to verify the hypothesis. In this retrospective cohort study, CHOP correlated with prolonged disease-free survival (HR = 0.385, 95 % CI 0.215–0.688;P= 0.001), whereas GRP78 showed an opposite association (HR = 4.573; 95 % CI 2.291–9.128;P< 0.001). Moreover, in a GRP78-positive subset, CHOP overexpression correlated with a lower risk of recurrence. In the receiver operating characteristic analysis, the prediction capability of the predictive model combining the above two markers surpassed that of the traditional model (P= 0.0085 for the area under the curve comparison). Within the anthracycline-treatment subgroup, the combined GRP78 and CHOP exhibited similar predictive significance. Cumulatively, our findings suggest a tight association between ER stress markers and clinical outcomes for patients with breast cancer.