Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
Med Oncol. 2012 Dec;29(5):3207-15. doi: 10.1007/s12032-012-0239-3. Epub 2012 Apr 29.
For breast cancer patients with lymph node metastasis, paclitaxel is the first-line chemotherapy drug. Clinical studies showed that some patients with breast cancer were insensitive to paclitaxel, which led to chemotherapy failure. Today, no validated markers exist for the prediction of chemotherapy sensitivity in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis. Epidemiological studies have also associated elevated tumor tissue TIMP-1 levels with a poor response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy. Additionally, our previous study proved that TIMP-1 significantly decreased the sensitivity of breast cancer cells to paclitaxel-induced apoptosis by enhancing degradation of cyclin B1. These data imply that TIMP-1 may be a useful predictive biomarker for chemotherapy resistance. In this retrospective study, we investigated the association between expression levels of TIMP-1 protein in the primary tumor and objective response to paclitaxel-based chemotherapy in 99 patients with breast cancer. With Kaplan-Meier survival analysis, the patients with high TIMP-1 levels were found to have significantly worse 5-year DFS (71.1 %) than the patients with low levels (88.5 %; P = 0.020). Similarly, the patients with high TIMP-1 levels had significantly worse 5-year OS (78.9 %) than patients with low levels (96.7 %; P = 0.004). In Cox's univariate and multivariate analyses, TIMP-1 was prognostic for both DFS and OS. Our data showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to paclitaxel-based chemotherapy, and TIMP-1 might be a potential biomarker for predicting response of breast cancer patients to paclitaxel-based chemotherapy.
对于有淋巴结转移的乳腺癌患者，紫杉醇是一线化疗药物。临床研究表明，部分乳腺癌患者对紫杉醇不敏感，导致化疗失败。目前，该患者群体中尚无预测化疗敏感性的验证标志物。组织金属蛋白酶抑制剂-1（TIMP-1）已被证明可防止细胞凋亡。流行病学研究还表明，肿瘤组织中 TIMP-1 水平升高与环磷酰胺/甲氨蝶呤/5-氟尿嘧啶和蒽环类药物化疗的反应不佳相关。此外，我们之前的研究证明，TIMP-1 通过增强细胞周期蛋白 B1 的降解，显著降低乳腺癌细胞对紫杉醇诱导的细胞凋亡的敏感性。这些数据表明 TIMP-1 可能是化疗耐药的有用预测生物标志物。在这项回顾性研究中，我们调查了 99 例乳腺癌患者原发肿瘤中 TIMP-1 蛋白表达水平与紫杉醇为基础的化疗客观缓解之间的关系。通过 Kaplan-Meier 生存分析，发现 TIMP-1 水平高的患者 5 年 DFS（71.1%）显著低于水平低的患者（88.5%；P=0.020）。同样，TIMP-1 水平高的患者 5 年 OS（78.9%）显著低于水平低的患者（96.7%；P=0.004）。在 Cox 单因素和多因素分析中，TIMP-1 对 DFS 和 OS 均具有预后意义。我们的数据表明，肿瘤组织中 TIMP-1 水平升高与紫杉醇为基础的化疗反应不良显著相关，TIMP-1 可能是预测乳腺癌患者对紫杉醇为基础的化疗反应的潜在生物标志物。
