Circular RNAs as central regulators of metabolic reprogramming and immune responses in the breast cancer microenvironment: A comprehensive review

Abstract

Circular RNAs (circRNAs) are becoming more widely acknowledged for their role in breast cancer (BC) and have emerged as significant regulators of a variety of biological processes. By sponging microRNAs (miRNAs), these covalently closed noncoding RNAs can function as competing endogenous RNAs (ceRNAs), encode peptides, and control the expression of parental genes. CircRNAs influence various cellular behaviors through these mechanisms. In vivo, they affect tumor growth and metastasis, while in vitro, they regulate BC cell proliferation, migration, invasion, and apoptosis. Certain circRNAs regulate fatty acid synthesis and uptake, leading to enhanced oxidative phosphorylation in mitochondria. They also modify glucose metabolism by controlling critical glycolytic enzymes and transporters, and stimulate lipid biosynthesis. Others use miRNA-mediated signaling axes to change the expression of glutamine transporters and metabolic enzymes, which in turn affects glutamine metabolism. Additionally, circRNAs influence important signaling pathways such as PI3K/AKT/mTOR, which promote improved cell survival and resistance to drugs. Certain circRNAs in the tumor microenvironment support the recruitment of myeloid-derived suppressor cells (MDSCs), encourage M2 macrophage polarization, and alter immune checkpoints by influencing T-cell activity and PD-L1 expression. Numerous circRNAs are promising biomarkers because of their strong correlations with clinicopathological parameters, treatment response, and prognosis. The classification, biological roles, immunoregulatory functions, and therapeutic potential of circRNAs in BC are compiled in this review.

Keywords: Breast cancer; Circular RNAs (circRNAs); Competing endogenous RNAs (ceRNAs); Drug resistance; Immune modulation; Metabolic reprogramming; MicroRNA (miRNA); PI3K/AKT/mTOR pathway; Tumor metabolism; Tumor microenvironment.