Increased claudin-4 expression is associated with poor prognosis and high tumour grade in breast cancer
Increased claudin-4 expression is associated with poor prognosis and high tumour grade in breast cancer
复制标题
DOI：
10.1002/ijc.24159
复制
发表时间：
2009-05-01
影响因子：
6.4
通讯作者：
Gallagher, William M.
中科院分区：
文献类型：
--
作者：
Lanigan, Fiona;McKiernan, Eadaoin;Gallagher, William M.
乳腺上皮细胞间紧密连接的作用传统上被认为是维持极性和屏障功能。然而，与正常上皮细胞相比，紧密连接蛋白claudin-4在乳腺肿瘤细胞中过度表达，这通常对应于极性的丧失。本研究的目的是调查claudin-4在乳腺癌中的分布和潜在的临床价值，并评估其作为预后和预测生物标志物的有效性。最初通过Western印迹分析检测了88例乳腺肿瘤中Claudin-4的表达，发现其与肿瘤分级呈正相关，与ER呈负相关。然后，通过免疫组织化学方法对组织微阵列上299个肿瘤的较大队列中Claudin-4的表达进行了评估。Claudin-4的表达与肿瘤分级、Hcr2呈正相关，与ER呈负相关。Claudin-4的高表达还与乳腺癌特异性生存率(p=0.0031)、无复发生存率(p=0.025)和总生存率(p=0.034)相关。多变量分析显示，claudin-4独立预测整个队列(HR1.95；95%CI1.01-3.79；p=0.047)和接受他莫昔芬佐剂治疗的ER阳性亚组(FIR4.34；95%C11.14-16.53；p=0.032)的生存。在295个乳腺肿瘤的DNA微阵列数据集中，claudin-4表达增加和不良结局之间的这种关系在mRNA水平得到了验证。我们的结论是，高水平的claudin-4蛋白与乳腺癌患者的不良结局有关，包括辅助剂三苯氧胺治疗的患者亚组。(C)2008年Wiley-Liss，Inc.
The role of intercellular tight junctions in breast epithelia[ cells is traditionaliy thought to be in maintaining polarity and barrier function. However, claudin-4, a tight junction protein, is overexpressed in breast tumour cells compared to normal epithelial cells, which generally corresponds to a loss in polarity. The aim of this study was to investigate the distribution and potential clinical value of claudin-4 in breast cancer, and to evaluate its usefulness as a prognostic and predictive biomarker. Expression of claudin-4 was initially examined by Western blot analysis in a cohort of 88 breast tumours, and was found to correlate positively with tumour grade and negatively with ER. Claudin-4 expression was then evaluated by immunohistochemistry in a larger cohort of 299 tumours represented on a tissue microarray. Claudin-4 expression correlated positively with tumour grade and Hcr2, and negatively with ER. High claudin-4 expression was also associated with worse breast cancer-specific survival (p = 0.0031), recurrence-free survival (P = 0.025) and overall survival (p = 0.034). Multivariate analysis revealed that claudin-4 independently predicted survival in the entire cohort (HR 1.95; 95%CI 1.01-3.79; p = 0.047) and in the ER positive subgroup treated with adjuvant tamoxifen (FIR 4.34; 95%C1 1.14-16.53; p = 0.032). This relationship between increased claudin-4 expression and adverse outcome was validated at the mRNA level in a DNA microarray dataset of 295 breast tumours. We conclude that high levels of claudin-4 protein are associated with adverse outcome in breast cancer patients, including the subgroup of patients treated with adjuvant tamoxifen. (C) 2008 Wiley-Liss, Inc.