DataSheet1_The Prognostic Value of the Developmental Gene FZD6 in Young Saudi Breast Cancer Patients: A Biomarkers Discovery and Cancer Inducers OncoScreen Approach.PDF

Wnt signalling receptors, Frizzleds (FZDs), play a pivotal role in many cellular events during embryonic development and cancer. Female breast cancer (BC) is currently the worldwide leading incident cancer type that cause 1 in 6 cancer-related death. FZD receptors expression in cancer was shown to be associated with tumour development and patient outcomes including recurrence and survival. FZD6 received little attention for its role in BC and hence we analysed its expression pattern in a Saudi BC cohort to assess its prognostic potential and unravel the impacted signalling pathway. Paraffin blocks from approximately 405 randomly selected BC patients aged between 25 and 70 years old were processed for tissue microarray using an automated tissue arrayer and then subjected to FZD6 immunohistochemistry staining using the Ventana platform. Besides, Ingenuity Pathway Analysis (IPA) knowledgebase was used to decipher the upstream and downstream regulators of FZD6 in BC. TargetScan and miRabel target-prediction databases were used to identify the potential microRNA to regulate FZD6 expression in BC. Results showed that 60% of the BC samples had a low expression pattern while 40% showed a higher expression level. FZD6 expression analysis showed a significant correlation with tumour invasion (p < 0.05), and borderline significance with tumour grade (p = 0.07). FZD6 expression showed a highly significant association with the BC patients’ survival outcomes. This was mainly due to the overall patients’ cohort where tumours with FZD6 elevated expression showed higher recurrence rates (DFS, p < 0.0001, log-rank) and shorter survival times (DSS, p < 0.02, log-rank). Interestingly, the FZD6 prognostic value was more potent in younger BC patients as compared to those with late onset of the disease. TargetScan microRNA target-prediction analysis and validated by miRabel showed that FZD6 is a potential target for a considerable number of microRNAs expressed in BC. The current study demonstrates a potential prognostic role of FZD6 expression in young BC female patients and provides a better understanding of the involved molecular silencing machinery of the Wnt/FZD6 signalling. Our results should provide a better understanding of FZD6 role in BC by adding more knowledge that should help in BC prevention and theranostics.

Wnt信号传导受体，如Frizzleds（FZDs），在胚胎发育和癌症过程中的多种细胞事件中扮演着关键角色。女性乳腺癌（BC）是目前全球发病率最高的癌症类型，导致六分之一与癌症相关的死亡。研究表明，FZD受体在癌症中的表达与肿瘤发展以及患者的预后，包括复发和生存率，密切相关。FZD6在乳腺癌中的作用尚未引起广泛关注，因此我们分析了沙特乳腺癌队列中FZD6的表达模式，以评估其预后潜力和揭示受影响的信号通路。约405名年龄在25至70岁之间的随机选取的乳腺癌患者的石蜡块经过自动化组织阵列器处理，然后使用Ventana平台进行FZD6免疫组织化学染色。此外，通过Ingenuity Pathway Analysis（IPA）知识库解码了FZD6在乳腺癌中的上游和下游调节因子。TargetScan和miRabel靶标预测数据库用于识别可能调节FZD6在乳腺癌中表达的microRNA。结果显示，60%的乳腺癌样本表现出低表达模式，而40%表现出较高的表达水平。FZD6表达分析显示与肿瘤侵袭（p < 0.05）存在显著相关性，与肿瘤分级（p = 0.07）存在边缘相关性。FZD6的表达与乳腺癌患者的生存结果高度相关。这主要归因于总体患者队列中，FZD6高表达肿瘤的复发率更高（DFS，p < 0.0001，log-rank）和更短的生存时间（DSS，p < 0.02，log-rank）。有趣的是，与疾病晚期发病的乳腺癌患者相比，FZD6的预后价值在年轻乳腺癌患者中更为显著。TargetScan microRNA靶标预测分析和miRabel验证表明，FZD6是乳腺癌中表达的一定数量microRNA的潜在靶点。本研究揭示了FZD6表达在年轻乳腺癌女性患者中的潜在预后作用，并加深了对Wnt/FZD6信号通路中涉及的分子沉默机制的理解。我们的研究结果应有助于提高对FZD6在乳腺癌中作用的认知，并为乳腺癌的预防和治疗提供更多知识。