Unearthing Regulatory Axes of Breast Cancer circRNAs Networks to Find Novel Targets and Fathom Pivotal Mechanisms

Circular RNAs (circRNAs) possess valuable characteristics for both diagnosis and treatment of several human cancers including breast cancer (BC). In this study, we combined several systems, biology tools and approaches to identify influential BC circRNAs, miRNAs, and related mRNAs as the members of competing endogenous RNAs (ceRNAs) networks and related RNA binding proteins (RBPs) to study and decipher the BC-triggering biological processes and pathways. Rooting from the identified total of 25 co-differentially expressed circRNAs (DECs) between triple negative (TN) and luminal A subtypes of BC from microarray analysis, five hub DECs (hsa_circ_0003227, hsa_circ_0001955, hsa_circ_0020080, hsa_circ_0001666, and hsa_circ_0065173) and top eleven RBPs (AGO1, AGO2, EIF4A3, FMRP, HuR (ELAVL1), IGF2BP1, IGF2BP2, IGF2BP3, EWSR1, FUS, and PTB) were explored to form the upper stream regulatory elements. All the hub circRNAs were regarded as a super sponge having multiple miRNA response elements (MREs). Then, three BC leading miRNAs (hsa-miR-149, hsa-miR-182, and hsa-miR-383) were also introduced from merging several established ceRNAs networks. The predicted 7- and 8-mer MREs matches between hub circRNAs and leading miRNAs ensured their enduring regulatory capability. The mined downstream mRNAs of the circRNAs-miRNAs network then were presented to STRING database to form the PPI network and to decipher the issue from another point of view. The BC interconnected enriched pathways and processes guarantee the merits of the ceRNAs network's members as targetable therapeutic elements. This study suggested extensive panels of novel therapeutic targets that are in charge of BC progression, hence their impressive role cannot be excluded and needs deeper empirical laboratory designs.