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

Abstract

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.

Editorial: Advances in genomic and genetic tools, and their applications for understanding embryonic development and human diseases

“…All accepted articles were divided into 3 categories. The results published in the first category of the RT supported the notion of previous reports showing that many genes function in a dual role manner in development and disease ( Gong et al, 2011 ; Teven et al, 2014 ; Sohn et al, 2016 ; Stepicheva and Song, 2016 ; Mahajan et al, 2021 ; McMillen et al, 2021 ; Assidi et al, 2022 ). Other reports showed that during development components of the FGF, Wnt, Notch, BPM, and Hedgehog signaling orchestrate crucial cellular events including proliferation, migration, differentiation, epithelial-mesenchymal transition (EMT), morphogenesis and somite myogenesis patterning.…”

Expression pattern, prognostic value and potential microRNA silencing of FZD8 in breast cancer

“…In conjunction to the miRNA prediction analysis carried out in the present study, the expression of another WNT receptor (FZD6) in BC was previously analyzed by the authors ( 74 ). It was demonstrated that the FZD6 prognostic value was more potent in younger patients with BC, which indeed is not the case for FZD8 expression.…”

“…In addition, at least 18 miRNAs were predicted to silence FZD6 expression, presented with a high prediction score. Specifically, the miRNAs were hsa-miR-101-3p, hsa-miR-302b-3p, hsa-miR-302d-3p, hsa-miR-372-3p, hsa-miR-373-3p, hsa-miR-520c-3p, hsa-miR-519a-3p, hsa-m i R-519b -3p, hsa-m i R-568, hsa-m i R-545 -3p, hsa-miR-130a-3p, hsa-miR-130b-3p, hsa-miR-301a-3p, hsa-miR-301b-3p, hsa-miR-454-3p, hsa-miR-3121-3p, hsa-miR-19a-3p, and hsa-miR-19b-3p (74). In this previous study by the authors, the predicted miRNAs that could target FZD6 expression were compared with those predicted to target FZD8 expression in BC.…”

Prognostic Role of M6A-Associated Immune Genes and Cluster-Related Tumor Microenvironment Analysis: A Multi-Omics Practice in Stomach Adenocarcinoma

“…FZD6, a member of the frizzled family, is a receptor for Wnts. There are numerous studies show that FZD6 expression is associated with the malignancy and prognosis of breast cancer, cervical cancer and human glioblastoma ( Zhang et al, 2021b ; Wang et al, 2021 ; Assidi et al, 2022 ). FZD6 also can inhibit the migration and proliferation of gastric cancer cells via targeting miR-21 to activate the non-classical Wnt pathway ( Yan et al, 2016 ; Ko et al, 2022 ).…”