Role of urokinase plasminogen activator and plasminogen activator inhibitor mRNA expression as prognostic factors in molecular subtypes of breast cancer.
Role of urokinase plasminogen activator and plasminogen activator inhibitor mRNA expression as prognostic factors in molecular subtypes of breast cancer.
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DOI：
10.2147/ott.s65344
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发表时间：
2014
影响因子：
4
通讯作者：
Müller V
中科院分区：
文献类型：
--
作者：
Witzel I;Milde-Langosch K;Schmidt M;Karn T;Becker S;Wirtz R;Rody A;Laakmann E;Schütze D;Jänicke F;Müller V
在乳腺癌的前瞻性随机试验中，尿激酶纤溶酶原激活物（uPA）及其抑制剂（PAI-1）的蛋白水平通过酶联免疫吸附法从新鲜冷冻肿瘤组织中测定，被评估为预后因素。然而，uPA和PAI-1在乳腺癌亚型中的作用以及这些因子的mRNA表达尚不清楚。我们使用Affymetrix HG-U 133A阵列在接受全身治疗（队列A， n=362）和未接受全身治疗（队列B， n=200）的乳腺癌分子亚组中评估uPA和PAI-1 mRNA的表达。我们验证了her2阳性乳腺癌患者队列中的mRNA表达（队列C， n=290）。通过ESR1和ERBB2 mRNA表达来定义Luminal、三阴性和her2阳性亚群。在整个队列A中，PAI-1而非uPA mRNA表达升高与较短的无病生存期相关（PAI为P=0.007， uPA为P= 0.069）。在不同分子亚组中，67% （n=244）的肿瘤为管腔肿瘤，14% （n=49）为her2阳性，19% （n=69）为三阴性。PAI-1 mRNA表达升高仅在her2阳性亚组中与较短的无病生存期相关（P=0.031）。uPA在her2阳性患者中的无病生存结果相同（P=0.011）。相比之下，在管腔或三阴性亚组中，没有观察到任何标记物与生存之间的关联。在her2阳性验证队列C中，uPA和PAI-1 mRNA表达升高也与较短的无病生存期密切相关（PAI-1的P=0.014， uPA的P<0.001）。本研究主要在her2阳性肿瘤患者中观察uPA和PAI-1表达对预后的影响。
Protein levels of urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) determined by enzyme-linked immunosorbent assay from fresh-frozen tumor tissue have been evaluated as prognostic factors in prospectively randomized trials in breast cancer. However, the role of uPA and PAI-1 in the context of breast cancer subtypes and for mRNA expression of these factors is less clear. We evaluated uPA and PAI-1 mRNA expression using the Affymetrix HG-U 133A array within molecular subgroups of breast cancer in cohorts of patients with systemic treatment (cohort A, n=362) and without systemic treatment (cohort B, n=200). We validated mRNA expression in a cohort of HER2-positive breast cancer patients (cohort C, n=290). Luminal, triple-negative, and HER2-positive subcohorts were defined by ESR1 and ERBB2 mRNA expression using predefined cutoffs. In the entire cohort A, elevated PAI-1 but not uPA mRNA expression was associated with shorter disease-free survival (P=0.007 for PAI and 0.069 for uPA). Regarding different molecular subgroups, 67% (n=244) of tumors were luminal, 14% (n=49) were HER2-positive, and 19% (n=69) were triple-negative. Elevated PAI-1 mRNA expression was associated with shorter disease-free survival only in the HER2-positive subgroup (P=0.031). The same disease-free survival results were found for uPA in HER2-positive patients (P=0.011). In contrast, no association between either marker and survival was observed in the luminal or triple-negative subgroups. In the HER2-positive validation cohort C, elevated uPA and PAI-1 mRNA expression also showed strong associations with shorter disease-free survival (P=0.014 for PAI-1, P<0.001 for uPA). In this study, the prognostic impact of uPA and PAI-1 expression was mainly observed in patients with HER2-positive tumors.