Juan Xu
Xiyi Chen
Yu Sun
Yaqian Shi
Fang Teng
Mingming Lv
Chen Liu
Xuemei Jia- 1Deparment of Gynecology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, China
- 2Department of Breast, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, China
- 3Department of Medical Genetics, Nanjing Medical University, Nanjing, China
Breast cancer is one of the most common malignant tumors in women worldwide. Circular RNA (circRNA) is a class of structurally stable non-coding RNA with a covalently closed circular structure. In recent years, with the development of high-throughput RNA sequencing, many circRNAs have been discovered and have proven to be clinically significant in the development and progression of breast cancer. Importantly, several regulators of circRNA biogenesis have been discovered. Here, we systematically summarize recent progress regarding the network of regulation governing the biogenesis, degradation, and distribution of circRNAs, and we comprehensively analyze the functions, mechanisms, and clinical significance of circRNA in breast cancer.
Introduction
Breast cancer is the most common female malignancy worldwide. According to authoritative cancer statistics in 2021 (1), breast cancer has become the most prevalent of all cancers. An abundance of epidemiological studies has led to the identification of a variety of risk factors for developing breast cancer, including age, family history, early menarche, late pregnancy and menopause, high estrogen level, and excessive dietary fat intake (2).
Breast cancer can be generally divided into four molecular subtypes according to the status of the expression of the joint hormone receptors (estrogen receptors [ER] and progesterone receptors [PR]) and of the human epidermal growth factor receptor 2 (HER2). These subtypes include Luminal A, in which hormone receptors are expressed but HER2 is not (ER+PR+HER2−); Luminal B, in which hormone receptors and HER2 are expressed (ER+PR+HER2+); HER2 overexpression, in which hormone receptors are absent but HER2 is expressed (ER-PR-HER2+); and triple negative breast cancer (TNBC), in which all of the noted receptors are absent (ER-PR-HER2−). Endocrine and targeted therapies can be effective for ER+ or HER2+ breast cancer patients. These treatments include the use of tamoxifen to block the effects of estrogen and trastuzumab to target HER2 receptors on breast cancer cells (3, 4). However, such treatments are ineffective for TNBC, and chemotherapy is regarded as the main systematic treatment for TNBC. Because the efficacy of chemotherapy is unsatisfactory, there exists a desperate need for effective therapies for TNBC (5). Therefore, it is important to explore new treatment regimens to improve current therapeutic strategies, especially for TNBC patients.
One potentially underappreciated class of biological molecules that may yield effective therapeutic targets is circular RNAs (circRNA). CircRNAs generally form single-stranded covalently closed circular structures by the joining of the 3′ and 5′ ends (6). Two key pathways leading to circRNA formation have been proposed in recent authoritative articles. One mechanism involves the backsplicing of exons during transcriptional activities; this splicing is facilitated by base pairing of reverse repeat elements, such as Alu elements, located in flanking introns or by RNA binding proteins (RBP). In another key mechanism, circRNAs can be generated from lariat precursors formed in exon-skipping events, as well as from intronic lariat precursors escaping from debranching (7–9). Approximately 80% of circRNAs come from the backsplicing of exons from precursor mRNA or lncRNA (10), but the first circRNA molecules to be discovered, viroids, were found more than 40 years ago to be produced independent of a backsplicing mechanism (11). No matter the mechanism of formation, circRNAs tend to have the following characteristics: (1) CircRNAs are widely and abundantly present in tissues and bodily fluids, and some circRNAs accumulate to a higher level than their respective linear counterparts because of their stable covalently closed structure (9). (2) Many circRNAs are evolutionarily conserved in eukaryotes, in part because they exert critical biological functions (8). (3) Specific circRNAs are typically expressed in a tissue- or cell-specific manner (8, 12).
Improvements in RNA sequencing technology have led to the identification of several types of circRNAs, including exonic circRNAs, which consist of only exon(s), exon-intron circRNAs (EIciRNA), which consist of both exon(s) and intron(s), and intronic circRNAs (CiRNA), which consist of only intron(s) (Figure 1). Cytoplasmic exonic circRNAs tend to have much longer intracellular half-lives compared with their linear counterparts (half-lives of circRNAs average approximately 48 h as opposed to roughly 10 h for many linear RNA molecules). A generally higher intracellular level of circRNAs than their linear counterparts results from this stability, and the stability can be explained at least partly by the resistance of circular RNA molecules to digestion by exonucleases (13, 14).
Figure 1 The biogenesis and function of circRNAs. There are three main types of circRNAs, including exonic circRNAs, which consist of only exon(s), exon-intron circRNAs (ElciRNA), which consist of both exon(s) and intron(s), and intronic circRNAs (CiRNA), which consist of only intron(s). An exon-intron circRNA can regulate the expression of its parental gene through binding to its promoter. The mechanism of regulation by exonic circRNAs include serving as a decoy for binding to microRNAs (miRNAs); interacting with specific binding elements on RBPs and acting as a sponge to regulate the functions of RBPs and to affect the activities of associated proteins; regulating transcription; and acting as templates to encode proteins.
Other characteristics that are specific to the size and sequence of particular circRNAs have also been discovered among exonic circRNAs. Jeck et al. have reported that the length of a given exon appears to influence circularization, a factor that is especially evident for those circles that consist of a single exon (15). Memczak et al. has shown that exonic circRNAs described to date generally involve the GT-AG pair of canonical splice sites (16). Moreover, the flanking intron sites that are involved in the backsplicing process generally have relatively long intron sequences, but some exceptions to the lengths of these sequences exist (9). Finally, the sequence of the circRNA can impact cellular localization and activity, as EIciRNA and CiRNA are mainly located in the nucleus and regulate the transcription of specific genes (17, 18).
The most well-established biological function of circRNA involves its serving as a decoy for binding to microRNAs (miRNAs). This activity of circRNA thus modulates the effects of miRNA effects on their target transcripts. In addition, circRNAs can interact with specific binding elements on RBPs and can act as a sponge to indirectly regulate the functions of RBPs and to affect the activities of associated proteins. Finally, circRNAs can recruit specific proteins to certain loci, such as promoter regions, so as to facilitate the transcription of their own host genes (8, 10). Interestingly, under certain circumstances, some circRNAs with internal ribosome entry site (IRES) elements and AUG sites have been reported to be translated into specific peptides, which points to their underestimated cap-independent translational potency (19) (Figure 1).
In recent years, regulators of circRNA biogenesis, degradation, and distribution have been identified with increasing rapidity. In addition, various types of circRNA have been found to be abnormally expressed in breast cancer, and their aberrant expression correlates with the occurrence, development, and prognosis of breast cancer; thus, circRNAs may be an important therapeutic target for breast cancer. In this review, we summarize the biogenesis, degradation, and distribution of circRNAs and the mechanisms of action of their regulators. We focus on cutting-edge discoveries concerning functions of circRNAs as well as associated mechanisms and their clinical significance in breast cancer.
The Regulators of circRNA Biogenesis
RNA Splicing Factor Regulates the Cyclization and Biogenesis of circRNA
CircRNAs are generally formed by backsplicing of mRNA from canonical splice sites (19). Because RNA splicing factors are central to this process, these factors are important to the regulation of circRNA biosynthesis. For example, Ashwal-Fluss et al. discovered that circRNA exon cyclization and canonical pre-mRNA splicing are mutually exclusive and that this competition is a tissue-specific and conservative mechanism of regulation of circRNA in animals (20). They found that a circular RNA related to the muscleblind gene (circMbl) and its flanking introns contain conserved binding sites for the MBL protein. Therefore, the level of MBL present strongly affects circMbl biosynthesis, and the authors confirmed that this effect depends on specific binding sites for MBL (20). Similarly, Pagliarini et al. found that SAM68 can bind to the distal intron inverted repeat Alu sequence of the spinal muscular atrophy gene (SMN), thereby supporting circRNA biosynthesis in vivo and in vitro (21). Splicing factor proline/glutamine-rich (SFPQ) is specifically enriched in introns flanking a type of Distal-Alu-Long-Intron (DALI) circRNA that is characterized by distal inverted Alu elements and long flanking introns, and depletion of SFPQ has been shown to significantly repress DALI circRNA production (22).
The importance of circRNA and its regulation have been demonstrated for several cancer types. Li et al. for example, found a global downregulation of circRNA levels in hepatocellular carcinoma. They further demonstrated that inhibition of the RNA splicing factor nudix hydrolase 21 (NUDT21) in this cancer type can promote the formation of circRNA and the production of UGUA sequences. Notably, UGUA sequences are crucial for circRNA formation, and thus this system establishes a positive feedback acceleration of circRNA production (23). In another carcinoma, oral squamous cell carcinoma, Zhao et al. found that circUHRF1 could bind to and inhibit miR-526b-5p and thus up-regulate the expression of c-MYC. Overexpression of c-MYC then facilitates the transcription of TGF-β1 and epithelial splicing regulatory protein 1 (ESRP1). Interestingly, ESRP1 itself targets flanking introns of circUHRF1, thereby accelerating circUHRF1 cyclization and biosynthesis (24). In gliomas, Liu et al. found that splicing factor serine and arginine-rich splicing factor 10 (SRSF10) can bind to Alu sequences of DNA surrounding a circular RNA related to ataxin-a (circATXN1) to regulate biosynthesis of this circRNA. Circ-ATXN1 levels were, therefore, decreased significantly upon knocking down of SRSF10 (25).
RNA Binding Proteins Regulate the Biogenesis of circRNA
Several other proteins with RNA binding activity have been shown to affect circRNA levels. For example, the immune factor NF90/NF110 contains double-stranded RNA binding domains and can bind to circRNA in the cytoplasm. In addition, however, the production of circRNA has been shown to increase upon association of nuclear NF90/NF110 with intronic RNA pairs flanking circRNA-forming exons. During viral infection, NF90/NF110 translocates from the nucleus to the cytoplasm, leading to a decrease in circRNA formation (26).
These regulatory abilities have, importantly, been shown to be important mediators in several developmental processes. In lung cancer, trinucleotide repeat-containing gene 6A (TNRC6A) can bind to introns near the exons that form circRNA to regulate production of circ0006916 (27). In induced pluripotent stem cell (iPSC) cells, the RNA binding protein fused in sarcoma (FU) can bind to introns near circular RNA reverse splicing sites to regulate circRNA biosynthesis (28). In prostate cancer, P53 can regulate activation of RNA binding motif protein 25 (RBM25), thus affecting the binding of RBM25 to circAMOTL1L. This binding is important for the induction of the biosynthesis of circAMOTL1L (29), because RBM25 mainly binds to the splicing complex, which in turn regulates selective splicing in combination with poly-G or exon splicing enhancer 5′- CGGGCA-3′ sequences (30, 31).
In TNBC, transcription factor E2F1 binds to the promoter of the gene that encodes septin-9 (SEPT9) and promotes the transcription of SEPT9 and the biogenesis of circSEPT9. Another transcription factor, EIF4A3, also regulates the biogenesis of circSETP9 by binding to the upstream and downstream sequences of the circSEPT9 exon (32). In hepatocellular carcinoma, RBM3 binds to SCD-circRNA 2 and regulates its biosynthesis, though the actual mechanisms underlying this regulation are not yet clear (33).
m6A Modification Regulates circRNA Biogenesis and Stability
Cis factors are also responsible for the control of biogenesis and stability of circRNAs. A recent study found that backsplicing occurs mostly at sites enriched in N-6-methyladenosine (m6A). For example, in male germ cells, approximately half of the circRNA molecules contain an m6A-modified initiation codon (34). Similarly, in macrophages of patients with acute coronary syndrome, knockdown of the N6-adenosine-methyltransferase METTL3 can down-regulate the m6A modification of hsa_circ_0029589 and promote biogenesis of this circRNA (35). Specifically relating to cancer, in hepatocellular carcinoma, m6A modification has been found to increase the cellular levels of circ_SORE by enhancing its stability (36).
Di Timoteo et al. found that m6A modification regulates the accumulation of circ-ZNF609 by regulating the back-splicing of circ-ZNF609, and they found direct correlations among a requirement for the presence of the METTL3 methyltransferase, binding of YTHDC1, and the back-splicing of the m6A modified exon (37), suggesting that methylation-mediated regulation might be a general phenomenon in circRNAs. Zhou et al. found that the m6A reader proteins YTHDF1, YTHDF2, and YTHDC1 bind to m6A-modified circRNA and that binding of YTHDF2 in particular reduces the stability of the circRNA (38). Thus, it can be concluded that m6A modification sites can function together with accessory proteins, including m6A writers, erasers, and readers, to control circRNA biogenesis.
The Regulation of circRNA Degradation
The levels of circRNA can be controlled at both the synthesis and degradation levels. It has been universally acknowledged that the degradation of most mRNAs initiates with poly(A)-tail shortening at the 3′ end, whereas some mRNAs undergo interior cleavage by endonucleases. Because of the lack of a 5′ 7-methylguanosine cap or a 3′ poly (A) tail, the cleavage of circRNAs, on the other hand, are generally dependent on endonucleases, which initiate degradation internally (39, 40). Cleavage of circRNA CDR1 by endonuclease AGO2 has been shown to be assisted by miR-671. This discovery served as the first evidence that some circRNAs can be degraded by endonucleases in a sequence-dependent manner (41).
In general, the pathways leading to circRNA degradation can be divided into five categories: miRNA-guided degradation, structure-mediated RNA decay (SRD), decay mediated by GW182 and its human homolog, specific m6A-modified circRNA decay and endoribonuclease RNaseL-mediated decay. Fischer et al. reported that the degradation of some highly structured circRNAs can be regulated by UPF1 and G3BP1, both of which recognize and unwind the overall structures of circRNAs (42). The absence of GW182, which is a key component of P body and RNAi complexes, can lead to the accumulation of endogenous circRNA and increase the steady state of cytoplasmic circRNAs, whereas the absence of other factors in the P body or RNAi complex has no similar effect (43). Further study indicated that the MID domain of GW182 protein may mediate the interaction between circRNAs and circRNA decay factors; the absence of TNRC6A, TRNC6B, or TRNC6C, which are the human homologs of GW182, in HEK293 cells, results in the same accumulation of steady-state circRNAs in human cells, indicating a conserved role of P-body and RNAi-mediated degradation of circRNA (43). Park et al. reported that m6A-modified circRNA can recruit the m6A reader protein YTHDF2 as well as the adaptor protein HRSP12, and HRSP12 can serve as the bridge to connect YTHDF2 with the endoribonuclease RNase P/MRP, thus enabling downregulation of m6A modified circRNA by RNase P/MRP (44). Liu et al. discovered that RNase L, a widely expressed cytoplasmic endoribonuclease, can be activated upon viral infection through an undefined mechanism and degrade the circRNAs with 16 to 26 bp RNA duplex (45) (Figure 2).
Figure 2 Mechanisms of circRNA degradation. (A) CircRNA CDR1 can be cleaved by endonuclease AGO2 with the assistance of miR-671 in a miRNA target sequence-dependent manner. (B) The degradation of highly structured circRNAs can be regulated by UPF1 and G3BP1, both of which recognize and unwind the overall structures of circRNAs. (C) m6A-modified circRNA can recruit the m6A reader protein YTHDF2 as well as the adaptor protein HRSP12, and HRSP12 can serve as a bridge to connect YTHDF2 with the endoribonuclease RNase P/MRP, thus enabling degradation of m6A modified circRNA by RNase P/MRP. (D) The absence of GW182 or its human homologue TRNC6A/B/C, the key component of P body and RNAi complexes, can lead to the accumulation of endogenous circRNA and increase the steady state of cytoplasmic circRNAs. (E) Upon viral infection, RNase L can be activated and can degrade circRNAs with RNA duplexes containing 16 to 26 bp through an undefined mechanism.
Regulators of circRNA Distribution
Once produced, the majority of circRNAs are transported to the cytoplasm where they exhibit further biological functions, whereas some intronic circRNAs and exon-intron circRNAs are thought to reside in the nucleus (17, 18). Since circRNAs lack the classical RNA transport sequence, the nuclear transport mechanism of circRNA remains unclear. As existing studies have indicated that the location of circRNAs determines their functions, it is important to continue to explore the potential mechanisms of circRNA nucleus export.
In order to explore circRNA nuclear transporting mechanisms, Li et al. knocked down 26 reported RNA transport-related proteins in Drosophila. Their results showed that one circRNA, with a length of 1120 bp, remained in the nucleus, whereas another circRNA, with a length of 490 bp, mainly localized to the cytoplasm after deletion of Hel25E. Both of these circRNAs mainly localize in the cytoplasm in wild-type Drosophila. The localizations of 12 other endogenous circRNAs that reside in the cytoplasm in wild-type Drosophila were further studied in Hel25E-knockout flies, and it was discovered that circRNAs with lengths of more than 811 bp mainly accumulated in the nucleus, whereas circRNA lengths of less than 702 bp resided in the cytoplasm in cells of the knockout Drosophila. An experiment exploring the human Hel25E homologs UAP56 (DDX39B) and URH49 (DDX39A), which share more than 90% similarity with Drosophila Hel25E, found that human UAP56 mainly regulates the nuclear transport of long circRNA (more than 1200 bp), whereas URH49 mainly regulates the nuclear export of short circRNA (less than 400 bp). Therefore, the nuclear accumulation of circRNA results mainly from defects of nuclear transport, and the length of circRNA is an important determinant that determines nuclear export (46, 47).
In addition, a very recent study found that m6A modification can also influence circRNA nuclear export. It was reported that circNSUN2 could bind to the m6A reader YTHDC1, which interacted with the m6A binding motif at the GAACU m6A within the splice junction of circNSUN2 (48). In studies of mRNA splicing, YTHDC1 has been shown to bind to the RNA splicing factors SRSF1, SRSF3, SRSF7, and SRSF10 to regulate mRNA splicing (49). YTHDC1 can also bind to SRSF3 and the classical nuclear receptor NXF1, thereby regulating the metabolism and transport of m6A modified mRNAs (50), suggesting that circRNA may also share the nuclear transporting mechanisms with mRNA.
CircRNA Profiles in Breast Cancer
By using high-throughput RNA sequencing and microarray analysis, profiles of circRNA expression in breast cancer have been comprehensively analyzed. The RNA sequencing or microarray data of circRNA expression profiles in samples related to breast cancer are listed in Table 1. Unlike the studies in gastric cancer and hepatocellular carcinoma that found more down-regulated circRNAs than up-regulated ones (30, 66), in breast cancer, more circRNAs have been found to be up-regulated. These results indicated that the regulation of circRNA levels is tissue specific and that circRNAs likely regulate different process in different systems.
Table 1 RNA sequencing and microarray analyses of differentially expressed circRNAs in breast cancer.
The Diverse Roles of circRNAs in Breast Cancer Progression and Associated Mechanisms
Mechanisms Leading to Oncogenic Functions of circRNAs in Breast Cancer
Most reported circRNAs have been proposed to function by acting as molecular sponges that bind to and inhibit the functions of miRNA molecules (67, 68). As shown in the RNA sequencing or microarray data, many circRNAs are dysregulated in breast cancer. Among them, the up-regulated circRNAs mainly function as oncogenic factors, whereas the circRNAs down-regulated in breast cancer generally play tumor suppressive roles. The circRNAs that play oncogenic roles in breast cancer are listed in Table 2. Here, we discuss several mechanisms through which circRNAs might influence the development or progression of breast cancer.
Table 2 CircRNAs that play oncogenic roles in breast cancer.
Acting as Competing Endogenous RNAs (ceRNAs)
A major mechanism that explains impacts of circRNA levels on cancer development involves the interaction of these RNA molecules with miRNA molecules. This binding event, called “sponging,” can inhibit the interactions of these miRNA molecules with other cellular molecules, frequently leading to inhibition of the miRNA activity. Thus, circRNAs can serve as ceRNAs. The downstream effect of the competition depends on the ultimate target of the miRNA itself.
Multiple circRNAs can target the same miRNA and thus assist malignant progression of breast cancer. For example, hsa_circ_0006528 and circCDR1as can target CCNE1 and RAF1, respectively, through sponging miR-7. In this way, both of these circRNA molecules promote the proliferation, invasion, migration, and chemoresistance of breast cancer cells (69, 70). Similarly, hsa_circ_0000291, hsa_circRNA_000518, and circ_TFF1 can target ETS1, FGFR1, and TFF1, respectively, through sponging miR-326, to accelerate the proliferation, colony formation, invasion, and migration of breast cancer cells; these activities also serve to reduce cell apoptosis (71, 72, 151). CircZNF609 and circIQCH can target DNMT3A and p70S6K1 by sponging miR-145 to promote the malignant phenotype of breast cancer cells (73, 74). Hsa_circ_0136666 and hsa_circ_0006528 can target CDK6 and CDK8 by sponging miR-1299, respectively, to regulate cell cycle progression, proliferation, apoptosis, invasion, migration, and drug resistance of breast cancer cells (75, 76). Hsa_circ_0052112 and hsa_circ_0001667 mainly regulates ZNF36 and FOXO3a by sponging target miR-125a-5p, respectively, to regulate the invasion and migration of breast cancer cells (77, 78). Circ-ABCB10 and circHMCU can sponge let-7 then regulate the expression of MCY, HMGA2, CCND1, and DUSP7, respectively, to promote the proliferation, invasion, migration, and chemoresistance of breast cancer cells (79, 80). CircPLK1 and hsa_circ_0000515 can target miR-296-5p to regulate the expression of PLK1 and CXCL10, respectively, to promote the growth, proliferation, migration and inflammatory response of breast cancer cells (81, 82). And surprisingly, hsa_circ_0011946 can interact with miR-26a/b to regulate RFC3, to promote the invasion and migration of breast cancer cells, whereas circWWC3 can interact with miR-26b-3p and miR-660-3p to regulate the expression of ZEB1, and thus promote the proliferation, invasion and migration of breast cancer cells (51, 83).
It is important to note the potential for ceRNA-acting circRNA molecules to improve patient outcomes in addition to their roles in cancer progression. For example, TV-circRGPD6 can interact with miR-26b. This interaction serves to regulate the expression of YAF2 and thus leads to a better prognosis (152).
Protein Decoy or Scaffolding Functions
In some cases, circRNAs may modulate the progression of breast cancer through direct or indirect interactions with RBPs. These interactions may alter the functions of the RBPs either through competition, with the circRNA serving as a decoy, or through the recruitment of other interacting factors, with the circRNA serving a scaffolding role. For example, in breast cancer cells with wild-type p53, circ-CCNB1 can interact with both p53 and H2AX, and Bclaf1 is free to bind to Bcl2. In p53-mutant breast cancer cells, on the other hand, H2AX is not able to interact with p53, and circ-CCNB1 is thus free to form a complex with H2AX and Bclaf1 and to thus to slow the development of p53 mutation-induced breast cancer progression (153). Similarly, circ-Dnmt1 can interact with p53 and AUF1 to facilitate their nuclear translocation, and this nuclear translocation of p53 induces autophagy. The nuclear translocation of AUF1 can increase mRNA stability and protein expression of Dnmt1, whereas the nuclear translocation of Dnmt1 further inhibits p53 transcription (84). In addition, CircSKA3 can interact with Tks5 and integrin-β1 to promote the invadopodium formation, thereby promoting breast cancer invasion (154).
Transcriptional Regulation
In at least one important case, circRNA has been shown to impact cellular biological functions via a direct impact on transcription in breast cancer. Specifically, circRNA FECR1 (a circRNA consisting of exons 2, 3, and 4 of the Friend leukemia integration 1 (FLI1) gene) has been shown to bind to the promoter of the gene encoding DNA methyltransferase 1 (DNMT1) and to down-regulate DNMT1 transcription. Similarly, circRNA FECR1 has been shown to recruit the methylcytosine dioxygenase TET1 to the promoter of FLI1 and thus to induce demethylation at the FLI1 promoter (85).
Encoding of Functional Peptides
One circRNA that is related to the growth factor receptor HER2 (circHER2) encodes a 103- amino acid peptide known HER2-103. This peptide promotes the binding of EGFR with HER2 and increases EGFR kinase activity. This activity has been shown to correlate with increased proliferation and invasion of breast cancer cells and to enhance sensitivity to pertuzumab (86).
Mechanisms Leading to Tumor Suppressive Functions of circRNAs in Breast Cancer
Consistent with the smaller number of circRNAs that are down-regulated in breast cancer, the number of known tumor suppressive circRNAs is much fewer than the oncogenic circRNAs in breast cancer. Similar to the mechanisms leading to enhancement of tumor development, these circRNAs may act as ceRNAs, protein decoys or scaffolds as well as encode functional peptides to suppress breast cancer progression. The known tumor suppressive circRNAs are listed in Table 3.
Table 3 CircRNAs with tumor suppressive functions in breast cancer.
ceRNAs
Both CircRNAs 000554 and circRNA_0025202 can sponge miR-182 to regulate the expression of ZNF36 and FOXO3a, respectively, and thus inhibit cellular proliferation, invasion, migration, and sensitivity to chemotherapy agents (155, 156). Similarly, circRNA-0001283 functions to sponge miR-187 to suppress HIPK3 expression, thus inhibiting the proliferation and invasion and promoting the apoptosis of breast cancer cells (157). CircTADA2A-E6 mainly regulates suppressor of cytokine signaling (SOCS) expression by sponging miR-203a-3p, and this sponging effect correlates with inhibition of breast cancer proliferation, invasion, and migration (52). CircASS1 mainly inhibits breast cancer invasion and migration by sponging miR-4443; it has also been found that the expression of circASS1 is inversely related with that of its parental gene arginosuccinate synthase 1 (ASS1), which indicates that the splicing of ASS1 mRNA and circASS1 may compete with each other (158). CircKDM4C mainly regulates the expression of phenazine biosynthesis like protein domain containing (PBLD) by sponging miR-548p, thereby inhibiting breast cancer growth, metastasis, and drug resistance (53). CircBMPR2 regulates ubiquitin specific peptidase 4 (USP4) expression by sponging miR-553, to inhibit breast cancer proliferation, invasion, migration, and tamoxifen resistance (159).
Protein Decoys or Scaffolds
Some tumor suppressive circRNAs function through interacting with proteins. For example, circ-Ccnb1 interacts with p53, inhibits tumor growth and increase the survival time of mice (153). Yi et al. reported the direct interaction between circRNA 0001073 and the RNA binding protein HuR (160). Experiments with the apoptosis-related protein receptor-interacting protein (RIP) revealed that the tumor suppressive circRNA circ-FOXO3, which is enriched in normal cells, can interact with MDM2, p53, and FOXO3, facilitating the formation of the MDM2-P53 complex while inhibiting MDM2-FOXO3 binding. This results in promotion of p53 ubiquitination and inhibition of FOXO3 degradation and thus the induction of apoptosis of breast cancer cells (161). Circular RNA-MTO1 can block the interaction between TRAF4 and Eg5, and suppress the translation of Eg5, to inhibit breast cancer growth and reverse the resistance of breast cancer cells to monosterol (162).
Encoding of Functional Peptides
circFBXW7 not only can interact with miR-197-3p, but also encodes a 185-amino-acid peptide that regulates the expression of FBXW7 and the degradation of c-Myc, thus inhibiting proliferation and migration of ovarian cancer cells (163).
Analysis of CircRNAs in the Diagnosis and Prognosis of Breast Cancer
Although circRNAs in plasma are not as stable as those within cells, circRNAs are still considered important diagnostic and prognostic biomarkers for cancer. CircRNAs that are particularly important diagnostic or prognostic biomarkers in breast cancer are listed in Table 4.
Table 4 CircRNAs with diagnostic and prognostic value in breast cancer.
As an example of this role, the analyses of several circRNAs can distinguish breast cancer tissues from noncancerous tissues. These distinctions have been shown to occur with favorable statistics, including having area under the curve (AUC) values greater than 0.7. These diagnostic circRNAs include the circular RNA VRK1 (AUC: 0.720, n = 350) (179), circIFI30 (AUC: 0.733, n = 38) (87), circSEPT9 (AUC: 0.711, n = 60) (32) and circAGFG1 (AUC: 0.767, n = 40) (54). In addition, the combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 has proven useful in diagnosis (AUC: 0.82, n = 51) (55). Although these circRNAs have been shown to be useful as tissue markers, to date, only hsa_circ_0001785 in the plasma has been shown to serve as potentially non-invasive biomarker for breast cancer (AUC: 0.771, n = 20; AUC: 0.784, n = 57) (182).
In addition to diagnostic potential, several circRNAs are prognostic biomarkers for breast cancer. For example, the expressions of circPLK1, circKIF4A, circEPSTI1, circGNB1, or circGFRA1 are associated with the tumor size and TNM stage of TNBC, whereas circPLK1, circKIF4A, circEPSTI1, or circGFRA1 are also associated with the lymph node metastasis of TNBC (56, 81, 88, 89). Similarly, high expression of circPLK1, circKIF4A, circEPSTI1, circGNB1, or circGFRA1 is associated with worse disease-free survival and overall survival in TNBC (56, 81, 88, 89).
Prospectives
Despite the rapid progress of our understanding of circRNA biogenesis and degradation over the last several decades, many important issues remain unresolved. For example, what signals regulate circRNA-specific expression? What are the intracellular or extracellular signals that activate the mechanisms leading to degradation of circRNAs? Why have only a few blood-localized circRNAs been identified as useful diagnostic markers?
Yet another important question involves potential roles of circRNAs in the communication between the tumor cells and the tumor microenvironment? Although many breast cancer-associated dysregulated circRNAs have been discovered and functionally characterized, most related studies have focused only on the roles of circRNAs on the proliferation, migration, invasion, apoptosis, and chemoresistance of tumor cells. However, tumor heterogeneity is a great challenge for therapeutic management, so growing attention has recently been paid to the molecules that mediate communication between tumor cells and cells of the tumor microenvironment, including cancer-associated fibroblasts, tumor-associated macrophages and T cells. Accordingly, further studies regarding the function of circRNA in mediating the dialogs that occur within or between tumor, stromal and immune cells have great future prospects.
Recently, with the development of ribosome nascent-chain complex (RNC) sequencing and ribo-sequencing, several circRNAs with coding potential have been discovered; however, only a few circRNAs with coding potential have been definitively identified, and most of these studies have indicated that the circRNA-encoded peptides, but not the circRNAs themselves, are the functional unit. Given the broad prospects of peptide therapeutics in the pharmaceutical industry, studies on tumor suppressive circRNA-encoded peptides may provide new directions for the development of drugs for breast cancer.
In addition, as noted in this study, different circRNAs can sponge the same miRNA, but these interactions tend to regulate the expression of different targets. These circRNAs, miRNAs, and targets form regulatory networks and thus promote or inhibit the progression of breast cancer. Therefore, the study of the circRNAs, miRNAs, and target networks in different systems is an important direction for future research.
Another important question involves mechanisms leading to the intracellular localizations of circRNAs. By analyzing the distribution of the tumor suppressive and oncogenic circRNAs in breast cancer (Table 2, Table 3), we noticed that most of the circRNAs with known function are mainly distributed in the cytoplasm. Five circRNAs, with lengths of 241, 318, 435, 473, and 571 bp, are distributed in both the cytoplasm and nucleus, and two circRNAs, of 269 and 342 bp, are mainly distributed in the nucleus. Similarly, at least 22 cytoplasm-localized circRNAs are less than 400 bp, and this phenomenon cannot be explained by transport mechanisms that solely involve the length of the circRNA, indicating that regulation of the localization of circRNAs is more complex than is currently appreciated.
Conclusion
CircRNAs form a large class of regulators of breast cancer progression. Clinical studies have also indicated that circRNAs are potential biomarkers for breast cancer diagnosis, prognosis, and therapy. However, the regulation network of circRNAs in breast cancer is still incompletely defined, and this uncertainty impedes the clinical exploitation of circRNAs. Future studies on the precise mechanisms of the key circRNA regulators and clinical relevance to breast cancer will further promote the clinical use of circRNAs and/or their relevant products in the management of breast cancer.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.
Author Contributions
JX wrote the manuscript text and prepared the tables. XC revised the manuscript and prepared the figures. CL and XJ provided advice and revised the manuscript. YuS, YaS, FT, and ML critically reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Funding
The study was financially supported by the National Natural Science Foundation of China (81902651), Jiangsu provincial key research and development program (BE2019621), Research Innovation Program for Graduates of Jiangsu Province (JX10413758, JX10413759).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.
The reviewer [ZW] declared a shared affiliation, with no collaboration, with the authors to the handling editor at the time of review.
Acknowledgments
We thank BioRender for providing the template for our figures.
Abbreviations
ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; BC, breast cancer; LA, luminal A; TNBC, triple-negative breast cancer; NMGT, normal mammary gland tissues; BCLM, breast cancer liver metastases; IPSC, induced pluripotent stem cells; HR, hormonal receptor; TNM, topography, lymph node, metastasis; OS, overall survival; DFS, disease free survival; RFS, recurrence-free survival; BCSC, breast cancer stem cell; EMT, epithelial–mesenchymal transition; PTX, paclitaxel; AUC, area under curve; DALI, distal-Alu-long-intron; SRD, structure-mediated RNA decay; RBP, RNA binding proteins; IRES, internal ribosome entry site; AUC, area under curve.
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Keywords: circRNA, breast cancer, biogenesis, degradation, distribution, oncogenic, tumor suppressive, biomarker
Citation: Xu J, Chen X, Sun Y, Shi Y, Teng F, Lv M, Liu C and Jia X (2021) The Regulation Network and Clinical Significance of Circular RNAs in Breast Cancer. Front. Oncol. 11:691317. doi: 10.3389/fonc.2021.691317
Received: 06 April 2021; Accepted: 23 June 2021;
Published: 09 July 2021.
Edited by:
Naoyuki Kataoka, The University of Tokyo, JapanReviewed by:
Zijuan Wu, Nanjing Medical University, ChinaLei Zhang, Qingdao University, China
Faryal Mehwish Awan, The University of Haripur, Pakistan
Copyright © 2021 Xu, Chen, Sun, Shi, Teng, Lv, Liu and Jia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xuemei Jia, xmjia@njmu.edu.cn; Chen Liu, liuchen@njmu.edu.cn