title: High expression of TIMP-1 in human breast cancer tissues is a predictive of resistance to paclitaxel-based chemotherapy.
abstract: 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.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Zhu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zha
authors.forename: Meiling
authors.initials: M
authors.lastname: Hu
authors.forename: Aidi
authors.initials: A
authors.lastname: Tao
authors.forename: Hangbo
authors.initials: H
authors.lastname: Zhou
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhou
authors.forename: Yujie
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D017239:Paclitaxel / Q000627:therapeutic use; D011379:Prognosis; D016016:Proportional Hazards Models; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019715:Tissue Inhibitor of Metalloproteinase-1; D017239:Paclitaxel