Assidi Mourad, Buhmeida Abdelbaset, Al-Zahrani Maryam H, Al-Maghrabi Jaudah, Rasool Mahmood, Naseer Muhammad I, Alkhatabi Heba, Alrefaei Abdulmajeed F, Zari Ali, Elkhatib Razan, Abuzenadah Adel, Pushparaj Peter N, Abu-Elmagd Muhammad
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Front Mol Biosci. 2022 Feb 14;9:783735. doi: 10.3389/fmolb.2022.783735. eCollection 2022.
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 ( 0.05), and borderline significance with tumour grade (). 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, 0.0001, log-rank) and shorter survival times (DSS, 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信号通路受体卷曲蛋白（Frizzleds，FZDs）在胚胎发育和癌症的许多细胞事件中起关键作用。女性乳腺癌（BC）是目前全球发病率最高的癌症类型，每6例癌症相关死亡中就有1例由其导致。研究表明，FZD受体在癌症中的表达与肿瘤发展以及包括复发和生存在内的患者预后相关。FZD6在乳腺癌中的作用鲜受关注，因此我们分析了其在沙特乳腺癌队列中的表达模式，以评估其预后潜力并揭示受影响的信号通路。使用自动组织阵列仪对约405例年龄在25至70岁之间随机选取的乳腺癌患者的石蜡块进行处理，制作组织微阵列，然后使用Ventana平台进行FZD6免疫组织化学染色。此外，利用 Ingenuity Pathway Analysis（IPA）知识库来解读乳腺癌中FZD6的上游和下游调节因子。使用TargetScan和miRabel靶标预测数据库来鉴定调节乳腺癌中FZD6表达的潜在微小RNA。结果显示，60%的乳腺癌样本呈现低表达模式，而40%表现出较高的表达水平。FZD6表达分析显示与肿瘤侵袭显著相关（P<0.05），与肿瘤分级具有临界显著性（P<0.1）。FZD6表达与乳腺癌患者的生存结果高度相关。这主要是由于在整个患者队列中，FZD6表达升高的肿瘤显示出更高的复发率（无病生存期，P<0.0001，对数秩检验）和更短的生存时间（疾病特异性生存期，P<0.02，对数秩检验）。有趣的是，与疾病发病较晚的患者相比，FZD6的预后价值在年轻乳腺癌患者中更为显著。TargetScan微小RNA靶标预测分析并经miRabel验证表明，FZD6是乳腺癌中大量表达的微小RNA的潜在靶标。本研究证明了FZD6表达在年轻乳腺癌女性患者中的潜在预后作用，并更好地理解了Wnt/FZD6信号通路中涉及的分子沉默机制。我们的结果应通过增加更多有助于乳腺癌预防和治疗诊断的知识，更好地理解FZD6在乳腺癌中的作用。
