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Abstract

Breast cancer (BC) is widely recognized as the most frequently diagnosed neoplasm among women worldwide. Despite significant advances, improved diagnosis and treatment of breast cancer have failed to translate into earlier detection or markedly better outcomes for patients, due to challenges including late-stage presentation, metastasis, recurrence, metabolic reprogramming, and drug resistance. Identifying reliable predictive indicators for early intervention and diagnostic markers remains a priority in breast cancer research, as this is crucial for improving patient prognosis. Circular RNAs (circRNAs), a class of non-coding RNAs (ncRNAs) abundant in various tissues and human cells, are established biomarkers for diagnosing and monitoring diseases such as those affecting the nervous, cardiovascular, and immune systems. CircRNAs contribute to tumorigenesis through the regulation of proliferation, metastasis, angiogenesis, and the tumor microenvironment. A growing body of evidence has established circRNAs as key regulators in breast cancer, elucidating their specific roles in driving tumor development and progression. Nevertheless, a more comprehensive understanding of the functional roles and molecular mechanisms of circRNAs in BC is essential and requires further research. This narrative review synthesizes the current knowledge on circRNAs encompassing their biogenesis, characteristics, methylation, tumor cell death, and selectively analyzes the translational potential of circRNAs in BC patients.

Keywords

autophagy metabolism methylation RNA binding protein immunotherapy

Introduction

Breast Cancer (BC) remains one of the most frequently diagnosed malignant tumors and a leading cause of cancer-related morbidity and mortality among women worldwide.^1–3 In the European Union (EU), the second leading cause of cancer death among females is breast cancer with age-standardised rates (ASRs) (13.3/100000) in 2025.⁴ EU breast cancer mortality has decreased by early prevention and precise treatment. In Fujian province of southeastern China, the age -standardized incidence rates (ASIRs) and mortality rates (ASMRs) of BC have respectively reached 46.41/100000 and 8.46/100000 for 2021-2025 by an Autoregressive Integrated Moving Average (ARIMA) model.⁵ This study shows that BC is still a public health challenge in China. The tumorigenesis of BC is multifactorial, driven by complex interactions among environmental, genetic, and hormonal influences.⁶ Advances in medical technology for BC have established diagnostic approaches that rely on imaging examinations, biomarker analysis, and tissue biopsy.^7–9 Current mainstay treatments for BC include surgery, radiotherapy, chemotherapy, endocrine (hormone) therapy, immunotherapy, and traditional Chinese medicine.^10–12 Despite significant improvements in these areas, BC continues to be a leading cause of cancer death, partly due to the lack of effective early diagnostic indicators. Moreover, the prognosis for BC patients remains poor, primarily because of challenges such as metastasis, relapse, metabolic reprogramming, and drug resistance.^13,14 Therefore, investigating the precise molecular mechanisms underlying BC and identifying non-invasive biomarkers are crucial for early diagnosis, accurate prognosis prediction, and the development of improved therapeutic strategies.

CircRNAs, a type of noncoding RNAs (ncRNAs) characterized by a covalently closed circular structure, were first discovered in the 1970s and are produced through back-splicing.^3,15 Like mRNAs, circRNAs are derived from precursor mRNAs (pre-mRNAs). Mechanistically, while mRNAs are produced via canonical splicing, circRNAs are derived through back-splicing and lack 5′ caps and 3′ polyadenylated tails.¹⁶ Due to their circular conformation, circRNAs possess inherent stability and are notably resistant to RNase R. Based on their biogenesis mechanisms, circRNAs are classified into three categories: exonic circRNAs (ecRNAs), circular intronic RNAs (ciRNAs), and exon-intron circRNAs (eiciRNAs). Ye et al. have demonstrated that the majority of circRNAs consist of exon-derived sequences.¹⁷ Back-splicing events, which covalently link exons within pre-mRNAs, give rise to exonic circRNAs. Their biogenesis primarily occurs through three mechanisms: lariat-driven circularization, intron-pairing-driven circularization, and RNA-binding proteins-driven circularization. Intronic circRNAs are generated from intronic lariat structures formed during pre-mRNA processing. Exon-intron circRNAs, which contain both exonic and intronic sequences, are produced in a similar manner to ecRNAs.

The dysregulation of circular RNAs facilitates tumor progression by perturbing critical cellular processes, notably including proliferation, migration, invasion and chemoresistance.^18–20 For instance, circRNA-104718 promotes hepatocellular carcinogenesis by sequestering miR-218-5p.²¹ In colon cancer, circNSUN2 enhances cancer cell migration by stabilizing HMGA2 mRNA via N⁶-methyladenosine (m⁶A) modification.²² Similarly, circNRIP1 fuels cervical cancer migration through sponging miR-629-3p and activating the PTP4A1/ERK1/2 pathway, thereby fostering metastatic potential.²³ Accumulating evidence indicates that circRNAs demonstrate subtype-specific dysregulation in BC. CircFRMD4A, regulated by p53, impedes cancer progression by inactivating pyruvate kinase PKM2, decreasing lactate production, and ultimately inducing glycolytic reprogramming and cuproptosis in colorectal cancer and BC.²⁴ By binding to FASN and inducing de novo fatty acid synthesis, circSpdyA ultimately inhibits NK cell activation in breast cancer.²⁵ CircACTN4 recruits TIP60 to enhance histone H4 acetylation at MYC target genes, thereby facilitating BC progression.²⁶ Therefore, the potential of circRNAs as biomarkers for both cancer diagnosis and prognosis is increasingly recognized.

Notably, circRNA expression profiles in BC are highly subtype-specific. To address the lack of a comprehensive synthesis in this area, this review aims to elucidate recent advances in circRNA research related to m⁶A and cell death, and to evaluate their clinical translation potential, with a primary focus on diagnostic and therapeutic applications for future directions.

Methodology

This narrative review drew on the databases of PubMed, Web of Science, and Google Scholar. The search of the literature on breast cancer and/or circRNA was conducted, covering publications up to December 2025. Meanwhile, this review was conducted in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) guideline.²⁷

The biological function of circRNA

CircRNA acts as a miRNA sponge

The regulatory role of miRNAs stems from their ability to bind target mRNAs with sequence complementarity, a process that induces mRNA degradation or translational repression to control gene expression. Simultaneously, circRNAs, which are predominantly localized in the cytoplasm, can function as miRNA sponges (Figure 1(a)). They achieve this role by harboring multiple competing binding sites known as microRNA response elements (MREs), which sequester miRNAs and counteract their regulatory functions.²⁸ Notably, ciRS-7, which contains 70 conserved miRNA binding sites and acts as a potent molecular sponge for miR-7, effectively inhibiting miR-7 bioactivity and its downstream functions.²⁹ Recently, accumulating evidence has revealed that ciRS-7, by efficiently sponging miR-7, plays a significant role in cancer development and progression, including BC, hepatocellular carcinoma and gastric cancer.^30,31 Hypoxia, a key characteristic of the tumor microenvironment, regulates multiple oncogenic progresses including tumor cell proliferation, invasion, angiogenesis, and metastasis. Hypoxia-inducible factor 1α (HIF1α), the central mediator of the hypoxia response, transcriptionally activates numerous oncogenic pathways that drive cancer progression under hypoxic conditions.³² In colorectal cancer, the sequestration of miR-125a-5p and miR-138-5p by circ-ERBIN alleviates the repression of 4EBP-1 translation, which in turn promotes HIF-1α expression and activation.³³ Similarly, circ-RanGAP1 promotes gastric cancer metastasis and invasion by targeting miR-877-3p, leading to the upregulation of VEGFA expression.³⁴ CircLMTK2 interacts with miR-150-5p to promote the proliferation and migration of gastric cancer cells through indirectly modulating c-Myc expression.³⁵ In contrast, some circRNAs exhibit tumor-suppressive roles. For example, circACVR2A sponges miR-626 to suppress bladder cancer proliferation and metastasis by regulating ETA4 expression.³⁶ Collectively, these findings demonstrate that the ability to act as miRNA sponges constitutes a common and crucial feature of circRNAs.

Figure 1.

The functions of circRNA in biological processes including miRNA sponging, RBPs binding, protein translation and transcription regulation (Created by BioGDP.com). (a) CircRNA can sponge miRNA to counteract the inhibition for mRNA, promoting more protein translation. (b) CircRNA can sponge or decoy RNA binding proteins (RBPs) with RBP motifs to regulate their functions. (c) CircRNA can directly enter ribosome to produce specific peptides in different microenvironment. (d) CircRNA can promote transcriptional regulation by interacting with the RNA polymerase II(Pol II).

CircRNA acts as a binding partner of RBPs

RNA-binding proteins (RBPs) bind to specific RNA sequences or structures to regulate their post-transcriptional fate, including stability, modification, and degradation. This diverse class includes proteins such as transcription factors and ribonucleoproteins. A growing body of evidence now indicates that RBPs influence circRNAs through multiple mechanisms (Figure 1(b)). For instance, SFPQ promotes Alu-independent circRNA biogenesis by facilitating the splicing of long introns.³⁷ Liao et al. demonstrated that p53, together with the RBP EWSR1, transcriptionally activates the formation of circFRMD4A.²⁴ Huang et al. reported that eukaryotic translation initiation factor 4A3 (EIF4A3) binds to the upstream region of the circZFAND6 pre-mRNA transcript and upregulates circZFAND6 expression in BC.³⁸ EIF4A3 has also been shown to promote the circularization of circ_0042881 by enhancing the back-splicing process in BC.³⁹ Additionally, specificity protein 1 (SP1) can enhance circSNX25 biogenesis, thereby promoting the initiation and progression of BC.⁴⁰

Meanwhile, several circRNAs have been shown to regulate the post-translational modification of RBPs through mechanisms such as ubiquitination, phosphorylation, and acetylation, thereby influencing protein degradation, activity, and subcellular localization. For example, circRNA-mTOR promotes hepatocellular cancer cell stemness by interacting with PSIP1 and facilitating its translocation from the cytoplasm to the nucleus.⁴¹ Research has established that circ-Foxo3 regulates cancer initiation and progression by assembling functional protein complexes. Du et al. demonstrated that circ-Foxo3 suppresses the cancer cell cycle by binding to both CDK2 and p21.⁴² Furthermore, circ-Foxo3 can interact with MDM2 and p53, thereby promoting tumor cell apoptosis.⁴³ In non-small cell lung cancer (NSCLC), m⁶A-modified circNDUFB2 was found to interact with TRIM25 and IGF2BPs, forming a TRIM25/circNDUFB2/IGF2BPs complex that promotes the ubiquitination and degradation of IGF2BPs.⁴⁴ Similarly, circFOXP1 binds to PTBP1 and protects PKLR mRNA from degradation, enhancing the Warburg effect and progression of gallbladder cancer.⁴⁵ Circ_GRHPR interacts with PCBP2 to facilitate FHL3 expression, thereby promoting proliferation and invasion in NSCLC.⁴⁶ Additionally, Yang et al. reported that circ-Amotl1 directly binds to and stabilizes the oncogene c-Myc, leading to its upregulation.⁴⁷

CircRNA function in protein translation

Traditionally, circRNAs were classified as non-coding RNAs because they lack 5′ caps and 3′ polyadenylated tails. Recently, emerging evidence indicates that some circRNAs contain functional open reading frames (ORFs) and can directly produce proteins through translation (Figure 1(c)).⁴⁸ In liver cancer, circβ-catenin undergoes translation to produce a previously unidentified 370-residue β-catenin isoform. By shielding full-length β-catenin from GSK3β-dependent phosphorylation and subsequent degradation, this isoform enhances β-catenin stability, ultimately resulting in activation of the Wnt/β-catenin signaling cascade.⁴⁹ Furthermore, circ-ZNF609, harboring a 753-nucleotide ORF spanning from the initiation to termination codons, was found to encode a novel ZNF609 protein isoform. This finding directly provides a clear example of endogenous translation capability by circular RNAs.⁵⁰ Song et al. demonstrated that circCAPG encodes a novel 171-amino acid polypeptide (CAPG-171aa), which can activate the MEKK2-MEK1/2-ERK1/2 pathway to regulate cell proliferation and metastasis in triple-negative breast cancer (TNBC).⁵¹

CircRNA function in transcriptional regulation

Acting as key regulators, some nuclear-enriched circRNAs orchestrate parental gene expression through transcriptional and post-transcriptional mechanisms (Figure 1(d)). U1 small nuclear ribonucleoproteins (snRNPs) in EIciRNAs bind U1 small nuclear RNA (snRNA) to form an EIciRNA–U1 snRNP complex. This complex interacts with RNA polymerase II at gene promoters to control parental gene transcription and expression.⁵² Ci-ankrd52 was reported to act as a positive regulator of RNA polymerase II (Pol II) transcription, thereby regulating the expression of its parent gene.⁵³

CircRNA and methylation

The methylation of adenosine at the N⁶ position is termed m⁶A modification. Substantial evidence indicates that m⁶A promotes the growth of malignant tumor cells, though its underlying regulatory mechanisms remain incompletely understood.⁵⁴ The regulation of m⁶A methylation influences nearly all stages of RNA metabolism, including transcription, maturation, translation, and decay.⁵⁵ Beyond linear mRNAs, m⁶A also modifies ncRNAs, such as miRNAs, lncRNAs, and circRNAs. Conversely, these ncRNAs can directly modulate m⁶A methylation levels, contributing to cancer pathophysiological processes.

First, multiple studies have demonstrated that the biogenesis and function of numerous circRNAs are regulated by m⁶A modification. For instance, Shao et al. reported that circAFF2, modified by m⁶A through ALKBH5 and recognized by YTHDF2, suppresses cullin neddylation to enhance radiosensitivity in colorectal cancer.⁵⁶ Similarly, circCCDC134 was significantly upregulated in cervical cancer tissues compared to adjacent normal tissues, a process driven by ALKBH5/YTHDF2-mediated m⁶A methylation that enhances its RNA stability.⁵⁷ In gastric cancer, circPAK2 was found to be highly expressed in tumor and metastatic lymph node tissues, and its nuclear export was facilitated by YTHDC1-mediated m⁶A modification.⁵⁸

Second, certain circRNAs can directly influence the m⁶A modification of miRNAs or mRNAs, thereby regulating cancer progression and therapy resistance. For example, circ0008399 promotes cisplatin resistance by enhancing TNFAIP3 expression through m⁶A-mediated stabilization of its mRNA.⁵⁹ Another circRNA, circEZH2 (hsa_circ_0006357), was identified via RNA sequencing and shown to be clinically relevant in colorectal cancer specimens. It was further found that circEZH2 binds to IGF2BP2, protecting it from ubiquitination and degradation, thereby stabilizing m⁶A-modified CREB1 mRNA and promoting oncogenesis.⁶⁰

CircRNA modulates cell death in cancer

CircRNA and autophagy

Autophagy facilitates tumor proliferation, metastasis, and invasion through the regulation of autophagy-related genes.⁶¹ Growing evidence indicates that circRNAs can influence autophagy by modulating the expression of key autophagy-related molecules such as Beclin1, LC3-II, and p62.⁶² For instance, circCDYL, which originates from the CDYL gene, was shown to act as a molecular sponge for miR-1275, leading to upregulation of ATG7 and ULK1 and thereby promoting autophagy in breast cancer.⁶³ Du et al. revealed that circ-Dnmt1 is highly expressed in breast cancer cells and facilitates the nuclear translocation of p53 and AUF1, subsequently enhancing autophagy and promoting Dnmt1 translation.⁶⁴ Similarly, circ-ABCB10 was found to promote autophagy by sequestering let-7a-5p, which results in increased expression of DUSP7.⁶⁵

In contrast, some circRNAs exert inhibitory effects on autophagy. CircROBO1 suppresses BECN1 transcription by sponging miR-217-5p and modulating downstream targets KLF5 and FUS, ultimately inhibiting autophagic activity.⁶⁶ Additionally, hsa_circ_0000199 was reported to inhibit autophagy through sponging miR-206 and miR-613, leading to activation of the PI3K/Akt/mTOR signaling pathway.⁶⁷

CircRNA and ferroptosis

Ferroptosis is a crucial form of iron-dependent cell death driven by oxidative damage, lipid peroxidation, and reactive oxygen species accumulation. In recent years, a growing body of studies has revealed that unusual ferroptosis is a vital part of carcinogenesis and poor prognosis in BC. Recently, some circRNAs have been shown as the participants to regulate the initiation and development of BC by inhibiting ferroptosis like VDAC3-derived crRNA (crVDAC3).⁶⁸ Zou et al. demonstrated that crVDAC3 is highly expressed in trastuzumab deruxtecan (T-DXd) resistance model. The T-DXd sensitivity of HER2-low breast cancer cells is weakened by upregulation of crVDAC3. Additionally, crVDAC3 upregulated the expression of HSPB1, which in turn suppressed the levels of ferroptosis in breast cancer cells, thereby diminishing the curative effect of T-DXd.⁶⁸ CircRNA_101093(cir93) was upregulated to promote ferroptosis-associated peroxidation in lung adenocarcinoma (LUAD).⁶⁹ Mechanistically, cir93 enhanced the interaction with fatty acid-binding protein to desensitize ferroptosis in LUAD cells.⁶⁹

CircRNA and pyroptosis

Pyroptosis is a recently characterized form of programmed cell death (PCD), distinguished by cellular swelling, large membrane bubble formation, and eventual plasma membrane rupture.⁷⁰ Accumulating evidence highlights the regulatory roles of circRNAs in this process. For instance, circPDIA3 suppresses pyroptosis by amplifying the autoinhibitory function of the GSDME-C domain through inhibition of its palmitoylation.⁷¹ Similarly, circERC1, encapsulated in extracellular vesicles (EVs) from pancreatic ductal adenocarcinoma (PDAC) cells after paclitaxel (PTX) treatment, counteracts gemcitabine/nab-paclitaxel (GEM-NabP)-induced pyroptosis.⁷² The mitochondria-localized circPUM1 was also shown to inhibit pyroptosis by modulating intracellular ATP levels.⁷³

Certain circRNAs promote pyroptotic cell death. CircMAP3K13 encodes a previously uncharacterized 26 kDa protein, MAP3K13-232aa, which binds directly to the kinase domain of IKKα, enhances its activity, and activates NF-κB signaling. This pathway upregulates NLRP3 expression and augments cisplatin-induced pyroptosis in gastric cancer (GC) cells.⁷⁴ In lung adenocarcinoma, inhibition of circ_0007312 mitigates osimertinib resistance by promoting pyroptosis and apoptosis via the miR-764/MAPK1 axis, highlighting a potential therapeutic target for overcoming drug resistance.⁷⁵ Additionally, icariin was shown to suppress GC cell viability and induce pyroptosis through the hsa_circ_0003159/miR-223-3p/NLRP3 pathway both in vitro and in vivo.⁷⁶ Furthermore, circNEIL3 enhances radiotherapy response by sponging miR-1184, which relieves repression of PIF1, leading to DNA damage and AIM2 inflammasome-mediated pyroptosis.⁷⁷

Conversely, some circRNAs exert anti-pyroptotic effects. Qingjie Huagong decoction inhibits pyroptosis in pancreatic acinar cells by modulating the circHipk3/miR-193a-5p/NLRP3 axis.⁷⁸ Similarly, circRPPH1 promotes lung adenocarcinoma progression by interacting with MAFK, upregulating SIRT1, and suppressing pyroptosis.⁷⁹

CircRNA and necroptosis

Necroptosis, a programmed cell death pathway that shares features of necrosis and apoptosis, can stimulate anti-tumor immunity and is increasingly studied as a means to modulate the tumor microenvironment.⁸⁰ For instance, TAK1 inhibition triggers RIPK1-mediated apoptosis and necroptosis in pancreatic cancer models, restraining PDAC progression without provoking significant inflammatory responses.⁸¹ In the vascular niche, PARylation of MLKL promotes angiocrine necroptosis, facilitating immune evasion.⁸² Meanwhile, the CXCR7 agonist TC14012 curbs lung cancer metastasis by blocking endothelial necroptosis via the CXCR7/RIPK3/MLKL axis.⁸³ Clofoctol also impairs gastric cancer stem cells by inducing TNF-mediated necroptosis via RanBP2 binding and β-catenin suppression.⁸⁴ Despite the current scarcity of evidence linking circRNA to necroptosis in tumors, this area holds promise as a future direction in cancer therapy.

The pathophysiology function of circRNA in BC

CircRNA and proliferation

Dysregulation of cell proliferation control is a hallmark of tumorigenesis. Recently, a growing body of evidence has implicated a novel class of circRNAs—with either oncogenic or tumor-suppressive functions—in breast cancer pathogenesis. These circRNAs primarily function by sequestering miRNAs or binding RBPs, thereby modulating downstream signaling cascades. For example, Zhao et al. reported that circACAP2, which is significantly upregulated in breast cancer, promotes tumor growth and metastasis via the miR-29a/b-3p/COL5A1 axis.⁸⁵ Through RNA sequencing of triple-negative breast cancer (TNBC) and normal tissues, Li et al. identified 229 differentially expressed circRNAs, including 180 upregulated and 49 downregulated species. Among these, circEIF3M was validated by qRT-PCR and shown to facilitate TNBC proliferation and invasion by sponging miR-33a, leading to CCND1 upregulation.⁸⁶ In addition, circSEPT9—whose expression is regulated by E2F1 and EIF4A3—promotes breast cancer proliferation and inhibits apoptosis via the circSEPT9/miR-637/LIF pathway.⁸⁷ Circ_0000511 acts as a miR-326 sponge to elevate TAZ expression, thereby accelerating proliferation and inhibiting apoptosis.⁸⁸ CircRHOT1 promotes malignant progression through the miR-106a-5p/STAT3 axis.⁸⁹ Other regulatory axes such as circ_0103552/miR-1236⁹⁰ and circ_0053063/miR-330-3p/PDCD4⁹¹ also play important roles in modulating breast cancer cell proliferation and apoptosis. Furthermore, Yang et al. revealed that hypoxia-induced circWSB1 promotes breast cancer progression by interacting with USP10 and destabilizing p53.⁹²

On the other hand, several circRNAs exert tumor-suppressive effects. CircKDM4B suppresses tumor growth by sponging miR-675 to upregulate NEDD4L expression⁹³. Similarly, circ_0068033, which is downregulated in breast cancer, suppresses tumor growth and invasion via the hsa_circ_0068033/miR-659 pathway.⁹⁴ Notably, Circ-BARD1—upregulated upon 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) treatment—inhibits proliferation and promotes apoptosis through the miR-3942-3p/BARD1 pathway.⁹⁵ The circ_0004771/miR-653/ZEB2 axis has also been reported to suppress proliferation and induce apoptosis.⁹⁶

CircRNA and metastasis

Accumulating evidence has established that circRNAs play critical roles in breast cancer metastasis (Figure 2). Zhou et al. identified differentially expressed circRNAs in primary breast cancer tissues compared with lung metastatic tissues using microarray analysis, revealing significant upregulation of circFBXL5 (hsa_circ_0125597) in metastatic samples. Mechanistically, circFBXL5 acts as a molecular sponge for miR-660, leading to increased SRSF6 expression. Functional experiments confirmed that silencing circFBXL5 markedly suppresses migration and invasion in breast cancer.⁹⁷ Similarly, Xing et al. reported that circIFI30 is highly expressed in TNBC, where it promotes epithelial–mesenchymal transition (EMT) and metastasis by binding miR-520b-3p and upregulating CD44.⁹⁸ In TNBC, Zeng et al. observed elevated expression of circANKS1B, which facilitates invasion and metastasis by inducing EMT. This pro-metastatic activity depends on its interaction with miR-148a-3p and miR-152-3p, leading to upregulation of USF1, subsequent TGF-β1 induction, and activation of the TGF-β1/Smad signaling pathway.⁹⁹ Other circRNAs also contribute to metastatic progression through miRNA sponging. For instance, circDENND4C knockdown under hypoxia was shown to suppress migration and invasion by elevating miR-200b/c levels.¹⁰⁰ circ_0005273 promotes tumorigenesis and metastasis by sponging miR-200a-3p, upregulating YAP1, and inactivating the Hippo pathway.¹⁰¹ Notably, Yang et al. revealed that circPSMA1 promotes metastasis and immunosuppression in TNBC via the miR-637/Akt1/β-catenin (cyclin D1) axis.¹⁰² Furthermore, circLIFR-007 facilitates hnRNPA1 nuclear export and enhances YAP phosphorylation, thereby inducing liver metastasis in breast cancer.¹⁰³ circMMP11 enhances proliferation, migration, and invasion while inhibiting apoptosis via the miR-625-5p/ZEB2 axis.¹⁰⁴ Additionally, the circRAD18–miR-208a/3164–IGF1/FGF2 axis promotes TNBC tumorigenesis and metastasis.¹⁰⁵ Several IGF-related pathways are also modulated by circRNAs. CircPLK1 upregulates IGF1 by binding miR-4500, thereby inducing migration and invasion,¹⁰⁶ while circGNB1 promotes TNBC metastasis by inhibiting miR-141-5p to enhance IGF1R expression.¹⁰⁷ Other mechanisms include the circ‐TFF1/miR‐326/TFF1 feedback circuit, which facilitates migration and invasion.¹⁰⁸

Figure 2.

The pathophysiological roles of circRNAs are schematically summarized in BC (Created by BioGDP.com). Specifically, circRNAs regulate BC tumorigenesis by modulating key cellular processes, including proliferation, invasion, metastasis, cell death, and chemoresistance.

In contrast, some circRNAs exert anti-metastatic effects: circRNA_000554 sponges miR-182 and upregulates ZFP36 to inhibit invasion and migration.¹⁰⁹

CircRNA and drug resistance

Resistance to adjuvant chemotherapy and radiotherapy represents a major clinical challenge in breast cancer management. Emerging evidence suggests that various circRNAs contribute to chemoresistance against agents such as tamoxifen, adriamycin, and paclitaxel (Figure 2).¹¹⁰ In adriamycin-resistant breast cancer, circ_0006528 is significantly upregulated and promotes resistance via the miR-7-5p/Raf1 axis.¹¹¹ Paclitaxel resistance has also been linked to circRNA activity: circ_0006528 promotes resistance via the miR-1299/CDK8 pathway,¹¹² whereas circRNA-MTO1—downregulated in monastrol-resistant cells—reverses resistance by binding TRAF4 and suppressing Eg5 expression.¹¹³

Additional mechanisms include circ-ABCB10, which enhances paclitaxel resistance through the let-7a-5p/DUSP7 axis,⁶⁵ and circWAC, which reduces paclitaxel sensitivity in TNBC by sponging miR-142 and activating the WWP1–Wnt/β-catenin pathway.¹¹⁴ CircAMOTL1 modulates apoptosis and paclitaxel resistance via AKT signaling,¹¹⁵ while circBMPR2 promotes tamoxifen resistance via the miR-553/USP4 axis.¹¹⁶ In HER2-positive breast cancer, circCDYL2 is upregulated in trastuzumab-resistant patients and may activate the GRB7–FAK pathway to sustain resistance.¹¹⁷ Moreover, tamoxifen resistance is facilitated by circ_UBE2D2, which is highly expressed in resistant models and transfers between cells via extracellular vesicles while sponging miR-200a-3p.¹¹⁸ Besides, chemotherapy-elicited exosomal circBACH1 promotes resistance through the miR-217/G3BP2 signaling pathway.¹¹⁹

Conversely, circKDM4C, which is downregulated in doxorubicin-resistant cells, enhances drug-induced apoptosis and suppresses resistance by protecting PBLD from miR-548p–mediated degradation.¹²⁰ For instance, downregulation of circRNA_0025202 confers tamoxifen resistance by regulating the miR-182-5p/FOXO3a axis, while its overexpression restores tamoxifen sensitivity both in vitro and in vivo.¹¹⁰

CircRNA and tumor metaboslim

Metabolic reprogramming is a hallmark of cancer initiation and progression. This aberrant metabolic activity supplies the additional nutrients and energy required for tumor growth and metastasis. However, the underlying mechanisms driving these metabolic alterations remain incompletely understood and warrant further investigation. CircSIPA1L3, a glucose metabolism-associated circRNA, was found to be differentially expressed in breast cancer tissues and serum. Analysis of 238 clinical specimens revealed its potential value as a prognostic biomarker in breast cancer patients.¹²¹ Mechanistically, circSIPA1L3 enhances glycolytic flux by upregulating the lactate exporter SLC16A1 and increasing glucose uptake. This effect is mediated through its interaction with IGF2BP3 to stabilize RAB11A mRNA, as well as its function as a molecular sponge for miR-665.¹²¹

CircRNA and tumor microenvironment

The tumor microenvironment (TME) plays a critical role in cancer progression, involving various components such as fibroblasts, stem cells, and immune cells. Exosomes serve as key mediators of intercellular communication within the TME by transferring bioactive molecules, including DNAs, mRNAs, non-coding RNAs, and proteins. For instance, exosomal circMMP11 has been shown to reduce lapatinib sensitivity in breast cancer cells via the miR-153-3p/ANLN axis.¹²² Similarly, Lu et al. demonstrated that exosomal circ_0001142 from breast cancer cells promotes M2 macrophage polarization by sponging miR-361-3p and upregulating PIK3CB.¹²³ CircHIPK3, highly enriched in breast cancer cell-derived exosomes, can be transferred to endothelial cells in the TME, where it sponges miR-124-3p to upregulate MTDH and promote angiogenesis.¹²⁴ Hypoxia, a common feature of breast cancer, also influences circRNA-mediated intercellular communication. Zhan et al. reported that circHIF1A is markedly upregulated in exosomes from hypoxic cancer-associated fibroblasts (CAFs) and can be internalized by breast cancer cells, where it enhances proliferation and stemness by sponging miR-580-5p and upregulating CD44.¹²⁵ In contrast, TV-circRGPD6 was found to suppress breast cancer stem cell-mediated metastasis by inhibiting CD44 and increasing p-H2AX levels through the miR-26b/YAP2 axis.¹²⁶ Under hypoxia, circPFKFB4 is highly expressed in MCF-7 cells, where it interacts with DDB1 and DDB2 to enhance CRL4DDB2 E3 ubiquitin ligase activity, leading to p27 degradation and tumor progression.¹²⁷

Additionally, circRNAs contribute to immune regulation in the TME. Zheng et al. revealed that high circWWC3 expression induces IL-4 secretion, promoting M2 macrophage polarization and immune escape, thereby accelerating breast cancer metastasis.¹²⁸ Furthermore, exosomal circCARM1 from cancer stem cells can be delivered to breast cancer cells, where it sponges miR-1252-5p to upregulate PFKFB2 and drive metabolic reprogramming.¹²⁹

Clinical applications of CircRNAs for patients with breast cancer

Due to the high morbidity and mortality associated with breast cancer, there is a critical need for effective potential biomarkers to enable early diagnosis and accurate prognosis. Circular RNAs (circRNAs) with significant differential expression offer several inherent advantages as cancer biomarkers (Table1). First, circRNAs are widely present not only in body fluids such as serum, plasma, and urine, but also in microvesicles and exosomes, allowing for convenient and noninvasive monitoring. Second, circRNAs are stable, abundant, and easily accessible in human cells. Third, differential expression patterns of circRNAs are observed across various tissues and at different stages of breast cancer. Fourth, circRNAs demonstrate high diagnostic sensitivity and specificity for breast cancer compared to traditional tumor markers such as CEA and CA153. Therefore, analyzing the clinical diagnosis and prognosis of breast cancer through circRNAs holds considerable clinical value and promising commercial prospects.

Table 1.

The dysregulation of circRNA and its function in BC.

CircRNA	Dysregulation	Sample types	Potential function	AUC	Ref
circSEPT9	↑	tissues	Diagnosis	0.711	⁸⁷
hsa_circ_0005046	↑	tissues	Diagnosis	0.77	¹³⁰
circWHSC1	↑	tissues	Diagnosis	0.968	¹³¹
circRREB1	↑	tissues	Diagnosis	0.707	¹³²
circ_0009910	↑	tissues	Diagnosis	0.7544	¹³³
circZCCHC2	↑	tissues	Diagnosis	0.787	¹³⁴
circCAPG	↑	tissues	Diagnosis	0.8723	⁵¹
circDNAJC11	↑	tissues	Diagnosis	0.658	¹³⁵
circPFKFB4	↑	tissues	Diagnosis	0.667	¹²⁷
circ_0007255	↑	serum	Diagnosis	0.7748	¹³⁶
circPRMT5	↑	serum	Diagnosis	0.9323	¹³⁷
circHMCU	↑	tissues	Prognosis	–	¹³⁸
circANKS1B	↑	tissues	Prognosis	–	⁹⁹
circSIPA1L3	↑	tissues	Prognosis	–	¹²¹
circATP2C1	↑	tissues	Prognosis	–	¹³⁹
hsa_circ_0000069	↑	tissues	Prognosis	–	¹⁴⁰
circ_0008717	↑	tissues	Prognosis	–	¹⁴¹
circPTK2	↑	tissues	Prognosis	–	¹⁴²
circ-EIF6	↑	tissues	Prognosis	–	¹⁴³
circRBMS3	↑	tissues	Prognosis	–	¹⁴⁴
circRNF20	↑	tissues	Prognosis	–	¹⁴⁵
circDUSP1	↓	tissues	Prognosis	–	¹⁴⁶
hsa_circ_001783	↑	tissues	Prognosis	–	¹⁴⁷
circWAC	↑	tissues	Prognosis	–	¹¹⁴
circTBC1D14	↑	tissues	Prognosis	–	¹⁴⁸
circ_0001006	↑	tissues	Prognosis	–	¹⁴⁹

Diagnostic biomarkers of circRNAs in breast cancer

A major clinical challenge in BC is that the majority of patients present with advanced-stage disease, for which curative therapies are scarce, underscoring the urgent need for early diagnosis. A growing body of evidence has validated that circRNAs, which are stable and easily detected in clinical samples like serum, are promising biomarkers for the early diagnosis of BC. Circ_0000615 and circ_0001785 demonstrate promising diagnostic potential, as evidenced by their area under the ROC curve (AUC) values in the serum of breast cancer patients reaching 0.904 and 0.784, respectively.^150,151 Furthermore, circ_0001785 expression was associated with histological grade, TNM stage, and distant metastasis.¹⁵¹ Elevated expression levels of circ_0005046 and circ_0001791 were observed in breast cancer tissues, with AUC values of 0.857 and 1.0, respectively.¹³⁰ In contrast, circAHNAK1 was downregulated in triple-negative breast cancer (TNBC) patients and correlated with TNM stage, recurrence-free survival, and overall survival.¹⁵² Li et al. screened serum from breast cancer patients using a ceRNA microarray and found that circ_0069094, circ_0079876, circ_0017650, and circ_0017526 were upregulated, proposing their potential utility as biomarkers.¹⁵³

Moreover, combining multiple circRNAs enhanced sensitivity, specificity, and diagnostic accuracy for breast cancer. For instance, the AUC values for upregulated circ-ELP3 and downregulated circ-FAF1 in serum samples were 0.733 and 0.787, respectively, but increased to 0.891 when combined, indicating superior diagnostic performance of circRNA panels over individual markers.¹⁵⁴ Similarly, the combination of upregulated circ_0000745, circ_0001531, and circ_0001640—with individual AUCs of 0.7998, 0.8258, and 0.7161, respectively—yielded a combined AUC of 0.913.¹⁵⁵ Additionally, circ_0006743, circ_0002496, and circ_0023990 have been identified as potential tissue biomarkers for breast cancer.¹⁵⁶

CircRNAs are also abundant and stable in exosomes, where they may participate in breast cancer progression and serve as novel diagnostic biomarkers. Liu et al. reported that circ_0000615 was highly expressed in the plasma of breast cancer patients, with an AUC of 0.904, sensitivity of 76.8%, and specificity of 88.4%.¹⁵⁰ Notably, exosomal circ_0000615 was significantly upregulated in breast cancer cells compared to breast epithelial cells, underscoring its potential as a biomarker for early breast cancer diagnosis.

While circRNAs hold promise as diagnostic biomarkers for BC, their clinical specificity and sensitivity remain to be firmly established, highlighting the need for extensive validation studies.

Prognostic value of circRNAs in breast cancer

Accumulating evidence indicates that circRNAs play a significant prognostic role in BC and hold promise as biomarkers for guiding adjuvant therapies, including chemotherapy, radiotherapy, and immunotherapy.

Yang et al. investigated the expression of circWSB1 in 100 paired breast cancer clinical specimens and observed its significant upregulation in tumor tissues compared with adjacent non-tumorous tissues. Clinicopathological analysis revealed a notable correlation between circWSB1 expression and the T stage of breast cancer patients. Furthermore, patients with high circWSB1 expression exhibited significantly shorter overall survival and a higher recurrence rate, suggesting the potential of circWSB1 as a prognostic biomarker for breast cancer.⁹² Similarly, high expression of circWAC and circPDCD11 in TNBC patients was associated with reduced overall survival and poorer prognosis.^114,157 In addition, TNBC patients with elevated circIFI30 expression tended to present with older age, higher histological grade, and more advanced clinical stage. Univariate analysis of overall survival confirmed that high circIFI30 expression served as an indicator of unfavorable prognosis.⁹⁸ Moreover, in HER2-positive breast cancer patients, circCDYL2 expression was positively correlated with recurrence rate and negatively correlated with both disease-free survival and overall survival.¹¹⁷

While current results identify circRNAs as promising prognostic biomarkers in BC, robust clinical validation with larger sample sizes remains essential.

CircRNAs as therapeutic targets for BC treatment

CircRNAs are increasingly recognized as diagnostic biomarkers and prognostic indicators for BC. A growing body of evidence suggests that circRNAs may also serve as promising therapeutic targets for BC. For instance, Wang et al. reported that circRNA-CREIT was significantly downregulated in doxorubicin-resistant TNBC. Restoration of circRNA-CREIT expression markedly enhanced doxorubicin sensitivity across multiple TNBC models, including cell lines, animal models, and patient-derived organoids.¹⁵⁸ Mechanistically, circRNA-CREIT acts as a scaffold protein that facilitates HACE1-mediated polyubiquitination and degradation of PKR, while also promoting RACK1/MTK1-dependent apoptosis through the suppression of stress granule formation.¹⁵⁸ These findings highlight the potential of circRNA-CREIT as a therapeutic target for overcoming chemoresistance in TNBC.

While circRNAs have been validated as therapeutic targets in preclinical models, the clinical translation of synthetic circRNAs has not been reported. Thus, clinical trials are warranted to evaluate their therapeutic potential in BC.

Prospection

The primary etiology of BC is complex and heterogeneous, and effective biological predictors remain elusive. Meanwhile, circRNAs are gaining increasing attention for their roles in tumor physiology, pathology, and therapy. The identification of hundreds of dysregulated circRNAs in BC has revealed their substantial potential as biomarkers for diagnosis, prognosis, and treatment. In this review, we discuss the circRNA from multiple aspects, including m⁶A modification, cell death (autophagy, ferroptosis, pyroptosis, and necroptosis), clinical prospect. However, the field presents new challenges that demand further exploration. Two major hurdles impede circRNA research. First, their accurate quantification is hampered by extremely low abundance in clinical samples, and current detection methods are prone to false positives or negatives, Second, a significant disconnect exists: although functional studies are progressing, the upstream regulatory mechanisms controlling circRNA biogenesis, turnover, and localization are still elusive.

Meanwhile, there is growing interest in circRNA vaccines as a novel clinical strategy. Their structural stability and sustained protein production position them as a promising therapeutic modality to inhibit tumor development and progression. The closed circular structure confers a superior capacity for both translation output and prolonged antigen presentation compared to linear mRNA, positioning circRNAs as highly attractive platforms for vaccine development. However, the translation of circRNAs into clinical applications faces challenges, including stringent purity requirements and a dependence on cold-chain logistics during storage and transport.

Conclusion

Currently, circRNAs make significant contributions to the diagnosis and prognosis of BC by serving as biomarkers detectable in tissue, blood, plasma and other non-invasive biopsies. Now, accumulating evidence indicates that circRNAs have potential as therapeutic targets in preclinical models of BC. Furthermore, a growing body of evidence suggests that circRNAs have revealed association with m⁶A modification, cell death and microenvironment in BC research. However, the specific functions and unknown mechanisms of circRNAs remain largely elusive in the BC progression. At the same time, the translation of circRNAs into clinical practice requires validation of their feasibility, effectiveness and safety through large clinical cohorts, as clinical trials in this field remain scarce. Ultimately, unlocking the clinical potential of circRNAs will depend on pivotal technological innovations and a deeper understanding of their lifecycle regulation, particularly the mechanisms controlling their initiation and degradation.

Footnotes

Acknowledgements

We thank DeepSeek for its support in language refinement during the preparation of this manuscript.

ORCID iD

Yang Shu

Author contributions

M.X. and Y.S. conceived the study; S.C and J.M drafted the manuscript and prepared the figures; Y.J.,Y.Z. and X.Z. reviewed the original draft and offered important opinion. All authors read and approved the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Social Development and Natural Science Foundation of Zhenjiang City, Jiangsu, China (No. FZ2023055, No. SH2023003, and No. SH2022044).

Declaration of conflicting interests

All authors declare that they have no competing interests in this paper.

Appendix

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The role of circRNAs in N 6 -methyladenosine(m 6 A),cell death and clinical applications in human breast cancer

Abstract

Keywords

Introduction

Methodology

The biological function of circRNA

CircRNA acts as a miRNA sponge

CircRNA acts as a binding partner of RBPs

CircRNA function in protein translation

CircRNA function in transcriptional regulation

CircRNA and methylation

CircRNA modulates cell death in cancer

CircRNA and autophagy

CircRNA and ferroptosis

CircRNA and pyroptosis

CircRNA and necroptosis

The pathophysiology function of circRNA in BC

CircRNA and proliferation

CircRNA and metastasis

CircRNA and drug resistance

CircRNA and tumor metaboslim

CircRNA and tumor microenvironment

Clinical applications of CircRNAs for patients with breast cancer

Diagnostic biomarkers of circRNAs in breast cancer

Prognostic value of circRNAs in breast cancer

CircRNAs as therapeutic targets for BC treatment

Prospection

Conclusion

Footnotes

Acknowledgements

ORCID iD

Author contributions

Funding

Declaration of conflicting interests

Appendix

References