Dias Kay, Dvorkin-Gheva Anna, Hallett Robin M, Wu Ying, Hassell John, Pond Gregory R, Levine Mark, Whelan Tim, Bane Anita L
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
PLoS One. 2017 Jan 3;12(1):e0168669. doi: 10.1371/journal.pone.0168669. eCollection 2017.
Claudin-low breast cancer is a molecular type of breast cancer originally identified by gene expression profiling and reportedly associated with poor survival. Claudin-low tumors have been recognised to preferentially display a triple-negative phenotype, however only a minority of triple-negative breast cancers are claudin-low. We sought to identify an immunohistochemical profile for claudin-low tumors that could facilitate their identification in formalin fixed paraffin embedded tumor material. First, an in silico collection of ~1600 human breast cancer expression profiles was assembled and all claudin-low tumors identified. Second, genes differentially expressed between claudin-low tumors and all other molecular subtypes of breast cancer were identified. Third, a number of these top differentially expressed genes were tested using immunohistochemistry for expression in a diverse panel of breast cancer cell lines to determine their specificity for claudin-low tumors. Finally, the immunohistochemical panel found to be most characteristic of claudin-low tumors was examined in a cohort of 942 formalin fixed paraffin embedded human breast cancers with >10 years clinical follow-up to evaluate the clinico-pathologic and survival characteristics of this tumor subtype. Using this approach we determined that claudin-low breast cancer is typically negative for ER, PR, HER2, claudin 3, claudin 4, claudin 7 and E-cadherin. Claudin-low tumors identified with this immunohistochemical panel, were associated with young age of onset, higher tumor grade, larger tumor size, extensive lymphocytic infiltrate and a circumscribed tumor margin. Patients with claudin-low tumors had a worse overall survival when compared to patients with luminal A type breast cancer. Interestingly, claudin-low tumors were associated with a low local recurrence rate following breast conserving therapy. In conclusion, a limited panel of antibodies can facilitate the identification of claudin-low tumors. Furthermore, claudin-low tumors identified in this manner display similar clinical, pathologic and survival characteristics to claudin-low tumors identified from fresh frozen tumor material using gene expression profiling.
紧密连接蛋白低表达型乳腺癌是一种最初通过基因表达谱鉴定出的分子类型的乳腺癌，据报道其与较差的生存率相关。紧密连接蛋白低表达型肿瘤已被认为优先表现为三阴性表型，然而只有少数三阴性乳腺癌是紧密连接蛋白低表达型。我们试图确定紧密连接蛋白低表达型肿瘤的免疫组化特征，以便在福尔马林固定石蜡包埋的肿瘤材料中便于对其进行识别。首先，收集了约1600个人类乳腺癌表达谱的电子数据集，并识别出所有紧密连接蛋白低表达型肿瘤。其次，确定紧密连接蛋白低表达型肿瘤与乳腺癌所有其他分子亚型之间差异表达的基因。第三，使用免疫组化检测这些差异表达最显著的基因中的一些在多种乳腺癌细胞系中的表达，以确定它们对紧密连接蛋白低表达型肿瘤的特异性。最后，在一组942例福尔马林固定石蜡包埋的人类乳腺癌中检测发现对紧密连接蛋白低表达型肿瘤最具特征性的免疫组化检测组合，这些病例有超过10年的临床随访，以评估这种肿瘤亚型的临床病理和生存特征。使用这种方法，我们确定紧密连接蛋白低表达型乳腺癌通常雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2（HER2）、紧密连接蛋白3、紧密连接蛋白4、紧密连接蛋白7和E-钙黏蛋白呈阴性。用该免疫组化检测组合识别出的紧密连接蛋白低表达型肿瘤，与发病年龄较轻、肿瘤分级较高、肿瘤体积较大、广泛淋巴细胞浸润和肿瘤边界清晰有关。与腔面A型乳腺癌患者相比，紧密连接蛋白低表达型肿瘤患者的总生存率更差。有趣的是，紧密连接蛋白低表达型肿瘤与保乳治疗后局部复发率较低有关。总之，一组有限的抗体可以便于识别紧密连接蛋白低表达型肿瘤。此外，以这种方式识别出的紧密连接蛋白低表达型肿瘤与使用基因表达谱从新鲜冷冻肿瘤材料中识别出的紧密连接蛋白低表达型肿瘤表现出相似的临床、病理和生存特征。
