Exosomal circRNAs: key modulators in breast cancer progression

Abstract

Breast cancer (BC) poses significant challenges globally, necessitating a deeper understanding of its complexities. Exosomes are cell-specific secreted extracellular vesicles of interest, characterized by a lipid bilayer structure. Exosomes can carry a variety of bioactive components, including nucleic acids, lipids, amino acids, and small molecules, to mediate intercellular signaling. CircRNAs are a novel class of single-stranded RNA molecules, characterized by a closed-loop structure. CircRNAs mainly exert ceRNA functions to intricately modulate gene expression and signaling pathways in breast cancer, influencing tumor progression and therapeutic responses. The unique packaging of circRNAs within exosomes serves as novel genetic information transmitters, facilitating communication between BC cells and microenvironmental cells, thereby regulating critical aspects of BC progression, immune evasion, and drug resistance. Besides, exosomal circRNAs possess the capabilities of serving as diagnostic and therapeutic biomarkers of BC, due to their stability, specificity, and regulatory roles in tumorigenesis and metastasis. Therefore, this review aims to elucidate the novel roles and mechanisms of exosomal circRNAs in BC progression, as well as their potential for diagnosis and therapeutics. The ongoing investigations of exosomal circRNAs will potentially revolutionize treatment paradigms and improve patient outcomes of BC.

Fig. 1. Exosome biogenesis and uptake mechanisms.

Exosomes originate from the inward budding of the endosomal membrane, forming early endosomes. These early endosomes mature into multivesicular bodies (MVBs), which then fuse with the plasma membrane to release exosomes into the extracellular space. Exosomes are characterized by a series of conserved proteins and specific biogenesis-related surface biomarkers, such as tetraspanins (CD9, CD63, CD81, CD82), biogenesis-related proteins (Alix, Tsg101), membrane transport and fusion proteins (Rabs, Annexins, Integrins), major histocompatibility complex (MHC), cytokine receptor, lipids. These markers are integral membrane proteins that play crucial roles in exosome stability, function, separation, and identification. Exosomes can be taken up by recipient cells through endocytosis (via clathrin-mediated or caveolin-mediated pathways), direct fusion with membrane, or receptor-ligand interactions involving surface proteins. The cargo of exosomes includes DNA, mRNA messenger RNA, ncRNAs non-coding RNAs, lipids, enzymes, and small molecules, enabling them to modulate a wide range of cellular functions and signaling pathways.

Fig. 2. The multifaceted roles of exosomal circRNAs in breast cancer progression, diagnosis, and drug resistance.

In cancer progression, circRNAs such as circSKA3, circPOKE, and circRHOT1 enhance tumor invasion, metastasis, and proliferation by modulating pathways like the USP10-Snail axis and miR-204-5p/PRMT5 axis. CircPSMA1 and circHSDL2 contribute to tumorigenesis and migration through interactions with key cellular pathways, including the miR-637/Akt1/β-catenin axis. Additionally, circSIPA1L3 and circCARM1 are involved in metabolic reprogramming, promoting glycolysis and tumor growth. In diagnosis application, circRNAs such as hsa-circRNA-0005795 and has_circ_0000615 emerge as promising biomarkers due to their differential expression in breast cancer patients. For drug resistance, circRNA-CREIT and circBACH1 play pivotal roles in modulating the sensitivity of breast cancer cells to treatments like paclitaxel and doxorubicin, impacting pathways such as the miR-217/G3BP2 axis. These circRNAs are integral to the modulation of tumor behavior, immune regulation, and therapeutic responses, providing valuable insights and targets for innovative breast cancer diagnostics and treatment strategies.