GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer
GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer
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DOI：
10.1158/0008-5472.can-06-1660
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Lee, Amy S.
中科院分区：
文献类型：
--
作者：
Lee, Eunfung;Nichols, Peter;Lee, Amy S.
发现化疗耐药的预测因子对于改善癌症患者的辅助治疗至关重要。78 kDa葡萄糖调节蛋白（GRP 78）被广泛用作未折叠蛋白反应（UPR）的指示剂，在肿瘤微环境中被诱导。体外研究表明，GRP 78赋予拓扑异构酶抑制剂，如阿霉素（阿霉素）的耐药性。在这里，我们报告了一项回顾性队列研究的127例II期和III期乳腺癌患者谁与阿霉素为基础的化疗治疗。存档肿瘤标本可用于分析，并检查GRP 78表达水平与“复发时间”（TTR）的关系，TTR用作耐药性的替代标志物。我们的数据显示，67%的研究受试者在开始化疗前在其肿瘤中表达高水平的GRP 78，并表明GRP 78阳性与较短的TTR之间存在关联[风险比（HR），1.78; P = 0.16]。有趣的是，亚组分析显示，GRP 78阳性组的HR在未接受进一步紫杉烷治疗的患者（HR，3.00; P = 0.022）和乳房切除术患者（HR，3.33; P = 0.027）中显著增加。在未接受进一步紫杉烷治疗的乳房切除术患者中，HR甚至更强（HR，4.82; P = 0.010）。使用GRP 78作为化疗反应性的预测因子以及GRP 78和/或UPR途径与紫杉烷的潜在相互作用需要更大规模的研究。
The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. In vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to "time to recurrence" (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; P = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies.