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Introduction: Triple-negative breast cancer (TNBC) is an aggressive type that lacks targeted therapies posing a challenge in its management. This necessitates identifying novel targets that may play a role in the regulation and progression of TNBC. There is renewed interest in targeting the androgen receptor (AR) since it is expressed in TNBC and plays an important role in its biology. Studies have shown that AR can influence the behavior of TNBC via affecting the of expression microRNA molecules (miRNAs), which can modulate the expression of cancer-regulatory proteins. We aimed to profile the expression of miRNAs in human TNBC tissue samples in relation to the expression of AR and investigate their prognostic value. Methods: The expression of 84 miRNAs in 24 TNBC tissue samples (12 AR-positive and 12 AR-negative) was examined using PCR array technology. Several bioinformatics tools were then utilized on the differentially expressed miRNAs (DE-miRNA) to determine the potentially affected protein targets and signaling pathways. Potential target genes (DEGs) for each miRNA were identified by miRWalk2.0. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for the target genes using the DAVID 6.8 bioinformatics tool. String and Cytoscape were used for establishing a PPI network and identifying the hub genes. Jamovi2.2 was used for the statistical analysis. Results: A total of 7 DE-miRNAs were found to be significantly expressed in the tissue samples relative to AR expression. Good and poor survival outcomes, respectively, were found to be linked to miR-328-3p and miR-489-3p. Interestingly, these two miRNAs were found to be up-regulated in AR-positive tumors. The association of miR-328-3p with AR corroborates our previous findings that this miRNA is up-regulated upon AR activation in TNBC cells. Two other miRNAs, miR-17-5p and iR-193b-3p, were found to be significantly associated with high T3 and low N2 status, respectively. Gene Ontology (GO) analysis for the 7 DE-miRNAs indicated a role in the regulation of the cell cycle in various cellular components (CC) such as the “nucleus”, “centrosome”, and “transcription factor complex”. GO analysis also showed enrichment in kinase and transcription factor activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses retrieved numerous relevant signaling pathways such as that of the TGF-beta, MAPK, Th17 cell differentiation, and endocrine resistance. Conclusion: This study offers an understanding of the molecular etiology of TNBC and further implicates miRNAs in mediating the effect of AR on TNBC. We also provide an integrative analysis of the AR-miRNA-TNBC gene network that can help in identifying potential therapeutic targets. Keywords: Breast Cancer, TNBC, Bioinformatics, miRNA, Androgen Receptor Citation Format: Bayan O. Abu Alragheb, Hassan Abushukair, Maysa Al-Husseini, Randa Bawadi, Mamoun Ahram. The association of androgen receptor with microRNA expression in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3772.

Background: Gliomas are the most common tumors arising from the brain. According to the WHO classification, gliomas are divided into low- and high-grade gliomas based on their aggressiveness and degrees of differentiation. Protocadherin Related 15 (PCDH15) gene is a member of the cadherin superfamily that encode membrane proteins involved in cell-cell adhesion. In this study, we aimed to investigate the prognostic value of PCDH15 expression in Low-Grade Gliomas (LGG) and Glioblastoma Multiforme (GBM). Methods: We conducted a bioinformatics analysis for PCDH15 in LGG and GBM patients’ data using their respective datasets from the Cancer Genomic Atlas (TCGA). GEPIA and GENT2 web-based tools were used to confirm the differential expression of PCDH15 in LGG and GBM patients in comparison with normal brain tissue. We used the cBioPortal database to compare PCDH15 expression across molecular and histological glioma subtypes. Also, the SurvExpress tool was used to assess the prognostic value of PCDH15 on overall survival (OS). To further understand the underlying molecular biology of PCDH15’s function, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for significantly co-expressed genes (|spearman correlation coefficient|≥ 0.5) with PCDH15 using the DAVID 6.8 bioinformatics tool. Results: LGG and GBM both had statistically significant differences in PCDH15 expression compared with normal brain tissue. PCDH15 expression was significantly higher in LGG patients compared with GBM patients (mean log2 (TPM + 1): 9.5 vs 5.6, P < 0.0001), with the highest expression in patients with mutated IDH genes. In the LGG cohort, higher PCDH15 expression was associated with longer OS (hazard ratio: 2.44, 95% confidence interval: 1.69 - 3.53, P = 1.949E-6) while no significant difference was found in the GBM cohort (hazard ratio: 1.07, 95% confidence interval: 0.74 - 1.53, P = 0.7304). GO analyses for co-expressed genes in LGG indicated a role in the biological process (BP) DNA-templated regulation of transcription with a cellular component (CC) in the nucleus and the molecular functions (MF) “histone demethylase activity”, “hydrolase activity, acting on acid anhydrides” and “zinc ion binding”. While in GBM, GO analysis showed enrichment in the BP terms, “neuron cell-cell adhesion”, “positive regulation of synapse assembly”, and the CC terms, “cell junction”, “axon”, “plasma membrane”. KEGG pathway analysis did not retrieve any significantly enriched pathways in both diseases. Conclusion: Our findings demonstrate a unique pattern of PCDH15 overexpression in low-grade gliomas which was translated into a substantial impact on patients’ survival. Functional enrichment analysis indicated transcription regulation as a potential mechanism for PCDH15 in LGG, further supporting PCDH15's potential as a therapeutic target. Citation Format: Hassan Mohammed Abushukair, Bayan Osama Abu Alragheb. Overexpression of protocadherin related 15 (PCDH15) gene predicts better prognosis in low-grade glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2727.

SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G>C), while the third family had compound heterozygous pathogenic variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management.