Logullo Angela Flávia, Pasini Fatima Solange, Nonogaki Suely, Rocha Rafael Malagoli, Soares Fernando Augusto, Brentani Maria Mitzi
Pathology Department, Federal University of São Paulo (UNIFESP), São Paulo, SP 04023-062, Brazil.
Radiology and Oncology Department (LIM24), São Paulo University, School of Medicine (FMUSP), São Paulo, SP 01246-903, Brazil.
Mol Clin Oncol. 2018 Oct;9(4):377-388. doi: 10.3892/mco.2018.1685. Epub 2018 Jul 27.
Molecular phenotyping and tissue microarray (TMA) studies have identified distinct invasive breast carcinoma subtypes: Luminal A, luminal B, enriched with overexpressed human epidermal growth factor receptor 2 (HER-2) and triple-negative, i.e., negative for HER-2, as well as for estrogen and progesterone receptor (ER and PR, respectively) expression. These subtypes are useful in clinical management, since they bear distinct prognoses and predictive responses to targeted therapy. However, although molecular profiling provides important prognostic indicators, breast cancer risk stratification remains a challenge in triple-negative cases. What is referred to as claudin-low subtype was identified as a triple-negative subset that is associated with more aggressive tumor behavior and worse prognosis. However, the immunohistochemical expression of claudins has not yet been standardized. Our objective was to verify whether the immunoexpression of claudins 4 and 7 (the main claudins specifically expressed in human breast tissue) in TMA is associated with survival and prognosis in luminal A, HER-2 and triple-negative molecular subtypes. In this diagnostic study, we investigated ER/PR receptor status, HER-2, claudin 4 and 7 expression and stem cell CD44/24 profiles, and verified the association with prognosis and survival outcomes in 803 invasive breast carcinoma cases arranged in four TMAs. Among these, 503 (62.6%) were positive for claudin 4 and 369 (46.0%) for claudin 7. Claudin 4 exhibited the lowest expression in luminal A and triple-negative subtypes, and the highest frequency of expression in HER-2-enriched subtypes, whereas claudin 7 staining was not associated with any subtype. The stem cell phenotype was not associated with subgroups or claudins 4 and 7. Claudin immunoexpression profile was not able to distinguish between patients with better or worse prognosis, and it was not correlated to triple-negative cases. Therefore, it may be concluded that the immunoexpression of claudins 4 and 7, individually or within the usual immunohistochemical context (ER, PR and HER-2), does not provide additional prognostic information on breast cancer subtypes.
分子表型分析和组织微阵列（TMA）研究已确定了不同的浸润性乳腺癌亚型：腔面A型、腔面B型、富含过表达人表皮生长因子受体2（HER-2）型和三阴性，即HER-2阴性，以及雌激素和孕激素受体（分别为ER和PR）表达阴性。这些亚型在临床管理中很有用，因为它们具有不同的预后以及对靶向治疗的预测反应。然而，尽管分子谱分析提供了重要的预后指标，但在三阴性病例中，乳腺癌风险分层仍然是一个挑战。所谓的claudin低表达亚型被确定为三阴性亚组，与更具侵袭性的肿瘤行为和更差的预后相关。然而，claudin的免疫组化表达尚未标准化。我们的目的是验证TMA中claudin 4和7（在人乳腺组织中特异性表达的主要claudin）的免疫表达是否与腔面A型、HER-2型和三阴性分子亚型的生存及预后相关。在这项诊断研究中，我们调查了ER/PR受体状态、HER-2、claudin 4和7的表达以及干细胞CD44/24谱，并在排列于四个TMA中的803例浸润性乳腺癌病例中验证了其与预后和生存结果的关联。其中，503例（62.6%）claudin 4呈阳性，369例（46.0%）claudin 7呈阳性。Claudin 4在腔面A型和三阴性亚型中表达最低，在富含HER-2亚型中表达频率最高，而claudin 7染色与任何亚型均无关联。干细胞表型与亚组以及claudin 4和7均无关联。Claudin免疫表达谱无法区分预后较好或较差的患者，且与三阴性病例无关。因此，可以得出结论，claudin 4和7的免疫表达，单独或在通常的免疫组化背景（ER、PR和HER-2）下，均不能为乳腺癌亚型提供额外的预后信息。
