Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma
Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma
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DOI：
10.1158/0008-5472.can-04-3765
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发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Ristimäki, A
中科院分区：
文献类型：
--
作者：
Heinonen, M;Bono, P;Ristimäki, A
HuR是一种广泛表达的mRNA结合蛋白。HuR的细胞内定位主要是核，但它穿梭于细胞核和细胞质之间。在细胞质中，它可以稳定某些转录本。由于HuR的核质易位是其活性所必需的，因此假设癌细胞中的胞质HuR表达可以是预后标志物。为了检测HuR在乳腺癌发生中的意义，我们研究了HuR在小鼠乳腺肿瘤模型和133例浸润性导管乳腺癌标本中的表达。在环氧合酶-2转基因诱导的小鼠乳腺肿瘤中，HuR表达升高，并且其在肿瘤细胞中的表达主要在胞浆中。在人类癌样本中，29%（38/133）的病例中发现了HuR的高细胞质免疫反应性。细胞质HuR表达与高级别（P = 0.0050）和肿瘤大小超过2 cm（P = 0.0082）相关。5年无远处转移生存率在高细胞质组为42% [95%可信区间（95%CI），26-58]，在高细胞质组为84%[95%可信区间（95%CI），26-58]。（95% CI，76-91），胞质阴性或低水平类别在考克斯多变量模型中，HuR的胞浆高表达是独立的预后因素（相对危险度2.07; 95% CI，1.05-4.07）。此外，单因素分析显示，在淋巴结阴性乳腺癌亚组中，高细胞质HuR免疫阳性与预后不良显著相关（P < 0.0007）。我们的研究结果表明，高细胞质HuR表达与乳腺导管癌的组织学分化差，肿瘤大小大，生存率低。因此，HuR是第一个mRNA稳定性蛋白，其表达与乳腺癌的不良结局相关。
HuR is a ubiquitously expressed mRNA-binding protein. Intracellular localization of HuR is predominantly nuclear, but it shuttles between the nucleus and the cytoplasm. In the cytoplasm it can stabilize certain transcripts. Because nucleocytoplasmic translocation of HuR is necessary for its activity, it was hypothesized that cytoplasmic HuR expression in cancer cells could be a prognostic marker. To test the significance of HuR in carcinogenesis of the breast, we have investigated HuR expression in a mouse mammary gland tumor model and from 133 invasive ductal breast carcinoma specimens. HuR expression was elevated in the cyclooxygenase-2 transgene-induced mouse mammary tumors, and its expression was predominantly cytoplasmic in the tumor cells. In the human carcinoma samples, high cytoplasmic immunoreactivity for HuR was found in 29% (38 of 133) of the cases. Cytoplasmic HuR expression associated with high grade (P = 0.0050) and tumor size over 2 cm (P = 0.0082). Five-year distant disease-free survival rate was 42% [95% confidence interval (95% CI), 26-58] in cytoplasm-high category and 84% (95% CI, 76-91) in cytoplasm-negative or -low category (P < 0.0001), and high cytoplasmic expression of HuR was an independent prognostic factor in a Cox multivariate model (relative risk 2.07; 95% CI, 1.05-4.07). Moreover, high cytoplasmic HuR inummopositivity was significantly associated with poor outcome in the subgroup of node-negative breast cancer in a univariate analysis (P < 0.0007). Our results show that high cytoplasmic HuR expression is associated with a poor histologic differentiation, large tumor size, and poor survival in ductal breast carcinoma. Thus, HuR is the first mRNA stability protein of which expression associates with poor outcome in breast cancer.