Saponaro Concetta, Scarpi Emanuela, Zito Francesco Alfredo, Giotta Francesco, Silvestris Nicola, Mangia Anita
Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.
Unit of Biostatistics and Clinical Trials, (IRST)-IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, 47014 Meldola (FC), Italy.
Cancers (Basel). 2019 Jul 22;11(7):1035. doi: 10.3390/cancers11071035.
The Wnt pathway is involved in the progression of breast cancer (BC). We aimed to evaluate the expression of some components of the Wnt pathway (β-catenin, FZD4 (frizzled receptor 4), LRP5 (low-density lipoprotein receptor-related protein 5), LRP6, and TCF1 (T-cell factor 1)) to detect potential associations with NHERF1 (Na+/H+ exchanger regulatory factor 1) protein. Besides, we assessed their impact on patients' clinical outcome. We evaluated 220 primary BC samples by immunohistochemistry (IHC) and protein localization by immunofluorescence. We found a significant correlation between NHERF1 and FZD4, LRP5, LRP6, and TCF1. Univariate analysis showed that the overexpression of β-catenin ( < 0.0001), FZD4 ( = 0.0001), LRP5, LRP6, and TCF1 ( < 0.0001 respectively) was related to poor disease-free survival (DFS). A Kaplan-Meier analysis confirmed univariate data and showed a poor DFS for cNHERF1+/FZD4+ ( = 0.0007), cNHERF1+/LRP5+ ( = 0.0002), cNHERF1+/LRP6+ ( < 0.0001), and cNHERF1+/TCF1+ phenotypes ( = 0.0034). In multivariate analysis, the expression of TCF1 and β-catenin was an independent prognostic variable of worse DFS ( = 0.009 and = 0.027, respectively). In conclusion, we found that the overexpression of β-catenin, FZD4, LRP5, LRP6, and TCF1 was associated with poor prognosis. Furthermore, we first identified TCF1 as an independent prognostic factor of poor outcome, indicating it as a new potential biomarker for the management of BC patients. Also, the expression of Wnt pathway proteins, both alone and in association with NHERF1, suggests original associations of biological significance for new studies.
Wnt信号通路参与乳腺癌（BC）的进展。我们旨在评估Wnt信号通路某些成分（β-连环蛋白、FZD4（卷曲受体4）、LRP5（低密度脂蛋白受体相关蛋白5）、LRP6和TCF1（T细胞因子1））的表达，以检测与NHERF1（钠/氢交换调节因子1）蛋白的潜在关联。此外，我们评估了它们对患者临床结局的影响。我们通过免疫组织化学（IHC）评估了220例原发性BC样本，并通过免疫荧光进行了蛋白定位。我们发现NHERF1与FZD4、LRP5、LRP6和TCF1之间存在显著相关性。单因素分析表明，β-连环蛋白（<0.0001）、FZD4（=0.0001）、LRP5、LRP6和TCF1（分别为<0.0001）的过表达与无病生存期（DFS）较差有关。Kaplan-Meier分析证实了单因素数据，并显示cNHERF1+/FZD4+（=0.0007）、cNHERF1+/LRP5+（=0.0002）、cNHERF1+/LRP6+（<0.0001）和cNHERF1+/TCF1+表型的DFS较差（=0.0034）。在多因素分析中，TCF1和β-连环蛋白的表达是DFS较差的独立预后变量（分别为=0.009和=0.027）。总之，我们发现β-连环蛋白、FZD4、LRP5、LRP6和TCF1的过表达与预后不良有关。此外，我们首次将TCF1确定为预后不良的独立预后因素，表明它是BC患者管理的新潜在生物标志物。而且，Wnt信号通路蛋白的表达，无论是单独还是与NHERF1联合，都为新研究提示了具有生物学意义的原始关联。
