Circular RNAs: New layer of complexity evading breast cancer heterogeneity

Abstract

Advances in high-throughput sequencing techniques and bioinformatic analysis have refuted the "junk" RNA hypothesis that was claimed against non-coding RNAs (ncRNAs). Circular RNAs (circRNAs); a class of single-stranded covalently closed loop RNA molecules have recently emerged as stable epigenetic regulators. Although the exact regulatory role of circRNAs is still to be clarified, it has been proven that circRNAs could exert their functions by interacting with other ncRNAs or proteins in their own physiologically authentic environment, regulating multiple cellular signaling pathways and other classes of ncRNAs. CircRNAs have also been reported to exhibit a tissue-specific expression and have been associated with the malignant transformation process of several hematological and solid malignancies. Along this line of reasoning, this review aims to highlight the importance of circRNAs in Breast Cancer (BC), which is ranked as the most prevalent malignancy among females. Notwithstanding the substantial efforts to develop a suitable anticancer therapeutic regimen against the heterogenous BC, inter- and intra-tumoral heterogeneity have resulted in an arduous challenge for drug development research, which in turn necessitates the investigation of other markers to be therapeutically targeted. Herein, the potential of circRNAs as possible diagnostic and prognostic biomarkers have been highlighted together with their possible application as novel therapeutic targets.

Keywords: Biomarkers; Breast cancer; CircrRNAs; Diagnosis; Heterogeneous tumor; Precision medicine; Prognosis.

Fig. 1

Classification of human genome according to coding potential. This figure represents a classification of human genome (DNA) where DNA includes coding sequences that are transcribed and translated into proteins and non-coding sequences that are only transcribed into RNA. Those RNA molecules are known as non-coding RNAs (ncRNAs) as they lose their coding capacity and to be translated into proteins. ncRNAs are further classified according to its function into housekeeping ncRNAs and regulatory RNAs.

Fig. 2

CircRNAs Biogenesis. This is a representative figure showing mature mRNA splicing and corresponding canonical biogenesis of circRNAs which might include B.1) direct back splicing. B.2) Intron pairing driven circularization, B.3) debranching resistant intron lariat and B.4) lariat-driven circularization (exon skipping).

Fig. 3

Different tumor suppressor and tumor promotor circRNAs in BC. This figure represents an array of tumor suppressor circRNAs and tumor promotor circRNAs with their respective target and their determining role in breast cancer.

Fig. 4

Different promising prognostic circRNAs in BC. This figure represents an array of circRNAs which are correlated to survival time, tumor size, TNM stage, and lymph node metastasis in BC representing promising BC prognostic biomarkers.