IPATIMUP, Institute of Molecular Pathology and Immunology of Porto University, Porto, Portugal.
Histol Histopathol. 2012 Oct;27(10):1283-95. doi: 10.14670/HH-27.1283.
The evaluation of claudins (CLDNs) expression pattern in tumours can be important to understand breast carcinogenesis. The study of CLDNs became more appealing since it was found that CLDN3 and CLDN4 are putative therapeutic targets for Clostridium perfrigens enterotoxin (CPE), as well as for monoclonal antibody-based therapy. Moreover, the recently characterized CLDN-low molecular subgroup of breast tumours increased the interest in these molecules. Based on these facts, our aim was to explore the pattern of expression of CLDNs among a large series of invasive breast carcinomas. We also analysed the correlation between the combinatorial expression of CLDN3/CLDN4 and classical prognostic factors and biological markers. In addition, we also compared the characteristics of tumours with low expression of CLDN3, CLDN4 and CLDN7, assessed by immunohistochemistry (IHC), and the ones from CLDN-low subgroup of tumours previously defined by genomic assays. The combinatorial analysis of the expression of CLDN3/CLDN4 showed a significant association between high CLDN3/CLDN4 levels and triple-negative tumours, as well as with worse patient outcome. This combined analysis may provide useful information for breast carcinomas, since these two CLDN members are putative therapeutic targets. Comparing tumours with low expression of CLDN3, CLDN4 and CLDN7 with tumours previously referred to as CLDN-low by genomic assays, we demonstrated that the single IHC evaluation of these three specific CLDNs is insufficient to identify the CLDN-low molecular subtype of breast tumours. The analysis of several other molecular markers, such as EMT (epithelial-to-mesenchymal transition) and CSC (cancer stem cell) markers should probably be added to improve the identification of this subgroup of tumours by IHC, which probably are enriched in carcinomas with metaplastic differentiation.
CLDNs（紧密连接蛋白）在肿瘤中的表达模式的评估对于理解乳腺癌的发生机制非常重要。CLDN3 和 CLDN4 是梭菌肠毒素（CPE）以及单克隆抗体治疗的潜在治疗靶点，因此 CLDNs 的研究变得更加引人注目。此外，最近鉴定的 CLDN-低分子亚组的乳腺癌增加了对这些分子的兴趣。基于这些事实，我们的目的是在大量浸润性乳腺癌中探索 CLDNs 的表达模式。我们还分析了 CLDN3/CLDN4 联合表达与经典预后因素和生物学标志物之间的相关性。此外，我们还比较了通过免疫组织化学（IHC）评估的 CLDN3、CLDN4 和 CLDN7 低表达的肿瘤的特征，以及通过基因组检测先前定义的 CLDN-低亚组肿瘤的特征。CLDN3/CLDN4 表达的组合分析显示，高 CLDN3/CLDN4 水平与三阴性肿瘤以及患者预后不良之间存在显著相关性。这种联合分析可能为乳腺癌提供有用的信息，因为这两个 CLDN 成员是潜在的治疗靶点。通过比较 CLDN3、CLDN4 和 CLDN7 低表达的肿瘤与通过基因组检测先前定义的 CLDN-低肿瘤，我们证明了对这三个特定 CLDN 的单一 IHC 评估不足以识别乳腺癌的 CLDN-低分子亚型。可能需要添加其他几个分子标志物的分析，如 EMT（上皮-间质转化）和 CSC（癌症干细胞）标志物，以通过 IHC 提高对该肿瘤亚组的识别，该亚组可能富含具有间变性分化的癌。
