- Open Access
Advances in circular RNAs and their roles in breast Cancer
© The Author(s). 2018
- Received: 28 January 2018
- Accepted: 8 April 2018
- Published: 29 August 2018
Circular RNAs (circRNAs) are a type of noncoding RNAs with a closed loop structure. With the development of high-throughput sequencing, massive circRNAs have been discovered in tumorous tissues. Emerging evidence suggests that the biological functions of circRNAs including serving as ceRNAs or miRNA sponges, interacting with proteins, regulating gene transcription and translation, suggesting that circRNAs will be novel biomarkers and targets for the diagnosis and prognosis of diseases. Breast cancer is the most frequently occurring cancer and the leading cause of cancer-related death among women worldwide. It is vital to understand the molecular pathways involved in the pathogenesis of proliferation and progression. In this review, we summarize the current knowledge on human circRNAs and their potential clinical implications on breast cancer.
- Circular RNA
- Breast cancer
Breast cancer is the most frequently occurring cancer and the leading cause of cancer-related death among women worldwide. It is estimated that there will be 255,180 new cases and 41,070 deaths of breast cancer in the United States in 2017 . The last few decades have witnessed outstanding advances in breast cancer treatment and a large number of trials have been performed to find an effective treatment strategy, but the morbidity and mortality are still high. It has been proven that obesity , estrogen and progestin use , advanced maternal age at first birth  and alcohol consumption  are associated with an increased risk of breast cancer by Epidemiological studies. Besides factors above, genetic mutations and epigenetic mechanisms are also important in the tumorigenesis of breast cancer [6, 7]. Thus, it is vital to understand the molecular pathways involved in the pathogenesis of proliferation and progression. Over the last few years, reports have indicated that many ncRNAs, such as miRNAs, are involved in the carcinogenic process and can be used as biomarkers for early risk stratification and long-term survival prediction [8, 9]. As anthor novel class of endogenous ncRNA , the involvement of circRNAs in breast cancer has also been explored.
Circular RNA (circRNA) is a type of recently re-recognized RNA, the detected amounts and types of which are increasing at a rapid rate. CircRNA was first discovered in RNA viruses via electron microscopy in 1976 . Subsequently, circRNAs were clearly observed in the eukaryotes by electron microscopy in 1979 . They range in length from a few hundred to thousands of nucleotides . Unlike linear RNAs that are terminated with 5’caps and 3’tails, circRNAs are single-stranded covalently closed circular transcripts . Unfortunately, these circRNAs were thought to be the results of mis-splicing or by-products of pre-mRNA processing with low abundance and only a small number of circRNAs in different organisms have been identified over the past 30 years . However, with the development and widespread use of high-throughput RNAsequencing (RNA-seq) technologies, as well as the development of specific algorithms for circRNA detection and quantification, circRNAs have recently been thrust into the spotlight as a newly appreciated class of non-coding RNAs. A large number of circRNAs have been successfully identified. Increasing evidence suggest that circRNAs are involved in the pathogenesis of a variety of diseases, such as neurological dystrophy , cardiovascular diseases  and cancer [18, 19]. In particular, circRNAs are reported to play important roles in tumorigenesis, metastasis, and therapy resistance . Moreover, due to the stability and tissue specificity of circRNAs in blood or plasma [20–22], they could act as dependable diagnostic molecular biomarkers of hepatocellular carcinoma , gastric cancer  and son on.
In this review, we summarize the current knowledge on human circRNAs and present an overview of the potential clinical implications of human circRNAs on breast cancer.
Biogenesis and regulation of circRNAs
Besides the circRNAs above, tRNA intronic circular RNAs (tricRNAs) are a class of abundant circular noncoding RNAs that are produced during metazoan tRNA splicing (Fig. 1E). This splicing mechanism is completely independent from that of pre-mRNAs. Biogenesis of tricRNAs requires anciently conserved tRNA sequence motifs and processing enzymes, and their expression is regulated in an age-dependent and tissue-specific manner [32, 33].
The biogenesis of circRNAs is regulated by various factors. Ashwal-Fluss et al.  have proved that circRNA are generated cotranscriptionally and their production rate is mediated by flanking intronic sequences . Zhang et al.  demonstrated that exon circularization is dependent on flanking intronic complementary sequences. What’s more, exon circularization efficiency can be regulated by competition between RNA pairing across flanking introns or within individual introns. Adenosine deaminase 1 actingon RNA (ADAR1), a RNA-editing enzyme, could suppress circRNA expression by melting the stem structure . That is, knockdown of ADAR1 induced elevated circRNA expression. A variety of RNA binding proteins (RBPs) have also been shown to induce the biogenesis of circRNAs. For instance, the alternative-splicing factor Quaking (QKI) protein was shown to modulate circRNA formation during the human epithelial–mesenchymal transition (EMT) . Mouseblind (MBL/MBNL1), a splicing factor, is thought to promote its own circRNA biogenesis from the second exon in Drosophila and humans by bingding MBL-binding sites in flanking introns .
In brief, the biogenesis of circRNAs is still unclear and how these factors control the circRNA circulation remains to be further investigated.
Functions of circular RNAs
Though the general mechanisms of circRNAs remain elusive, increasing evidences have reported that circular RNA participate in series of pathophysiology process.
CircRNAs serve as ceRNAs or miRNA sponges
A circRNA named CDR1as, well known as ciRS-7, harboring more than 70 conserved binding sites and is highly expressed in human and mouse brains was first reported to function as a sponge of miR-7 . Another circRNA called Sry (sex-determining region Y) was reported to serve as a sponge for miR-138 , thus regulating the invasion, development and metastasis of tumor cells. What’s more, a recently discovered circRNA, called cirITCH, similarly acts as a miRNA sponge via miR-7 and miR-20 . All these findings above indicate that circRNAs could function as miRNA sponges to contribute to the regulation of cancers.
However, a recent study by Militello G et al. proved that few circRNA could function as ‘miRNA sponge’ . Thus, as a classical model of circRNA function, ‘miRNA sponge’ is becoming more and more controversial.
CircRNAs bind and sequester proteins
CircRNA molecules could specifically bind to protein molecules directly or through RNA as well as sequester proteins to block the protein effects by working as competing elements (Fig. 2G). An example of the function of circRNA to interact with proteins is circFoxo3. CircFoxo3, preferentially expressed in the cytoplasm versus the nucleus , was found to interact with the anti-senescence proteins ID1 and E2F1 and the anti-stress proteins FAK and HIF1a, causing them to be retained in the cytoplasm, preventing their nuclear translocation to inhibit their antisenescence and anti-stress functions . Another study by the same research group showed that circFoxo3 is able to bind to the cell cycle proteins cyclin-dependent kinase 2 (CDK2) and cyclin-dependent kinase inhibitor 1 (p21), resulting in the formation of a circ-Foxo3-p21-CDK2 ternary complex, suppressing the cell cycle and blocking the transition from G1 to S phase . Other studies further proved circRNAs bind and sequester proteins. Ashwal-Fluss et al. proved that circMbl can sequester excess MBL to regulate the production balance of the mbl and circMbl . Abdelmohsen et al. proposed that the extensive binding of CircPABPN1 to HuR prevents HuR binding to PABPN1 mRNA and lowers PABPN1 translation .
Consider the examples above, we could put forward an interesting possibility that ceRNAs including lncRNAs, circRNAs as well as other molecules may interact with each other with RNA binding protein shared response elements in the cytoplasm.
Regulating gene transcription
Although most circRNAs regulate miRNAs as the role of miRNA sponge, some circular RNAs could cis or trans regulate gene transcription (Fig. 2H). Researchers found that, knockdown of ciRNAs, which exists in the nucleus and have little enrichment for microRNA target sites led to the reduced expression of their parent genes. Importantly, ci-ankrd52 and ci-sirt7 can function as positive regulators of their parental gene transcription by interacting with Pol II , which indicating that intron circular RNAs can regulate parental gene transcription. Exon-intron circRNAs (EIciRNAs), have also been shown to function as transcription factors. Li et al. found that both of the two exon-intron circular RNAs, circ-EIF3J and circ-PAIP2, can combine with the U1 small nuclear ribonucleic proteins (snRNPs) to further interact with RNA Polymerase II in the promoter region of the host gene to enhance the expression of their parental genes in HeLa and HEK293 cells . As a result, EIciRNAs can play an important role in positive feedback regulation. In addition, the ecRNA, circANRIL, may reduce the content of ANRIL protein, regulating the expression of INK4/ARF . In summary, circRNA could regulate gene expression by combining RNA polymerase II complex and transcripting related proteins.
Due to without 5′–3′ polarity and polyadenylated tail as well as lacking internal ribosome entry site (IRES), most researchers believed that circRNAs were a distinct class of endogenous noncoding RNAs that could not translate proteins. However, considering that most circRNAs are generated from coding genes and contain complete exons, a few circRNAs were proven to have the potential to be translated into proteins (Fig. 2I). Studies of Chen et al. have shown that after inserting an internal ribosome entry site (IRES) into a synthetic circRNA, the eukaryotic ribosomal 40S subunit would bind to circRNAs at the IRES and initiate the translation process, both in vitro and in vivo . Also, green fluorescent protein (GFP) can produce extremely long protein chains by transfecting an artificial circRNA inserted with a GFP open reading frame in Escherichia coli . Importantly, viral circRNA is known to encode proteins in eukaryotic cells. For example, circRNAs in hepatitis D virus (HDV) could encode the hepatitis D virus antigen (HDAg) after infecting eukaryotic cells . Additionally, A recent study of Legnini I. et al. found that circ-ZNF609 could translate proteins in murine myoblasts when driven by IRES . Pamudurti N. R. et al. found circMbl3 could translate protein in fly heads . In summary, more and more evidence proved that circRNAs could translate proteins directly. However, these discoveries showed that notion of circRNAs being non-coding RNAs is doubtful.
Early studies showed that circRNAs are differentially expressed in many cancerous tissues and massive circRNAs have been discovered in tumorous tissue with the development of high-throughput sequencing, including in breast cancer, suggesting that circRNAs may be exploited for diagnostic and therapeutic applications.
Expression of circRNA in breast cancer
Circular RNA in breast cancer
CircRNA and the proliferation and progression of breast cancer
circRNA regulates the proliferation and progression of breast cancer via serving as microRNA sponges
Accumulating evidence have proved that miRNAs regulate gene expression in most biological processes, including in carcinogenesis. In depth study revealed that some circRNAs may function as microRNA sponges in regulating the proliferation, metastasis and invasion of cancer. For example, some studies have shown the essential role of miR-124-3p as a tumor suppressor in breast tumorigenesis . CircHIPK3, an abundant circRNA derived from Exon2 of the HIPK3 gene, was observed to sponge to 9 miRNAs with 18 potential binding sites via a luciferase screening assay. Specifically, they show that circHIPK3 binds to miR-124 directly and inhibits miR-124 activity, inducing the proliferation of breast cancer . The study of Tang et al.  reveals that the circRNA, hsa_circ_0001982, is markedly overexpressed in breast cancer tissue and cell lines. Furtherly, they performed loss-of-function and rescue experiments to investigate the biological and miRNA ‘sponge’ functions of hsa_circ_0001982 in the tumorigenesis and progression. Results revealed that hsa_circ_0001982 knockdown suppressed breast cancer cell proliferation and invasion and induced apoptosis by targeting miR-143, providing a novel insight for breast cancer pathogenesis. In a similar way, results of another study discovered a significantly up-regulated circRNA hsa_circ_0008717 in breast cancer tissue and they nominate it as circ-ABCB10 . In follow-up RT-PCR validation, the significant up-regulation of circ-ABCB10 was confirmed in a larger sample size and cell line. In vitro, loss-of-function experiments showed circ-ABCB10 knockdown suppressed the proliferation and increased apoptosis of breast cancer cells, revealing the important regulatory role of circ-ABCB10 through sponging miR-1271 . CircGFRA1 has been reported upregulated in breast cancer and was positively correlated with tumor size, TNM staging, lymph node metastasis and histological grade of TNBC . Further experiments showed that circGFRA1 could promote proliferation and inhibit apoptosis in TNBC. Researchers proposed that circGFRA1 might function as miR-34a sponge to regulate GFRA1 expression through the ceRNA mechanism . Researches above establishe a novel approach whereby circRNAs can regulate the progression of cancer through sequestering specific miRNA species associated with proliferation, differentiation, migration and carcinogenesis process.
CircRNA regulates the proliferation and progression of breast cancer via cancer-associated signaling pathways
CircRNA as potential diagnostic and prognostic biomarkers in breast cancer
It is well known that most cancer types can be cured, if diagnosed at an early stage. The molecular pathogenesis of breast cancer is complex and shows heterogeneous. Considering the currently used cancer diagnostic markers including CT, MRI and histopathology are invasive or expensive, minimally invasive and inexpensive methods are imperatively required. Besides, prognostic evaluation also plays a significance role in early intervention of poor prognostic factors as well as the prolongation of the life expectancy of cancer patients. Recent studies have shown that circRNAs are involved in multiple pathological processes of breast cancer. The clinical potential for use of circRNAs as diagnostic and prognostic biomarkers for breast cancer is increasingly being investigated. According to the current studies, the main characteristics of circRNAs are as the following: (1) Diversity: more than 100,000 circRNAs have been identified in human tissues detected by high-throughput sequencing . (2) Highly abundant expression: circRNAs comprise over 14% of the transcribed genes in fibroblasts. Although the overall abundance of circRNAs is low, the expression of some circRNAs is much higher than that of linear RNAs . (3) Stability: without 5′-3′ polarity and polyadenylated tail, circRNAs are more stable than liner RNA and can resist to degradation by RNA exonuclease or RNase R . In addition, the half-life of circRNAs in most species is longer than 48 h, while the average half-life of mRNAs is 10 h . (4) Specificity: circRNAs show cell type-specific and tissue-specific expression . (5) Universality: a report in 2012 confirmed that circRNAs are the most common molecules after linear RNAs in human cells . (6) Conservatism: the signal behind circularization seems to be evolutionarily conserved in different species . Hence the properties above confer distinct advantages to circRNAs as potential biomarkers of cancer diagnosis and prognosis in breast cancer.
For example, the plasma levels of hsa_circ_0001785 in post-operative patients were significantly decreased compared to pre-operative patients , showing the important role to be a prognosis biomarker. This phenomenon might be mainly due to the decreasing release of tumor-derived nucleic acid after mammary tumor excision . Besides, hsa_circ_0001785 plasma level was closely related to histological grade, TNM stage and distant metastasis, which helps to the staging and grading of breast cancer. What’s more, hsa_circ_0001982  and circ-ABCB10  knockdown suppressed the proliferation and increased apoptosis of breast cancer cells, CircGFRA1 has been reported upregulated in breast cancer and was positively correlated with tumor size, TNM staging, lymph node metastasis and histological grade of TNBC . The above examples are only a fraction of the several instances in which circRNAs have demonstrated promising diagnostic and prognostic potential in breast cancer. However, more studies are required before circRNAs can be recommended for human use.
Therapeutic potential of circRNAs in breast cancer
CircRNAs exhibit potential anti-cancer effects
Currently, a number of circRNAs have been proved associated with proliferation and progression of breast cancer, manifesting their potential roles as targets in breast cancer therapy. The recent study of Wang et al. reveal that circRNA-000911 plays an anti-oncogenic role in breast cancer by serving as a miRNA sponge for miR-449a and thereby promoting the function of Notch1 and the NF-κB signaling pathway . Therefore, the overexpression of circRNA-000911 may provide a future direction which may aid in the development of a novel treatment strategy for breast cancer. The capacity of circ-Foxo3 in inducing cell apoptosis and inhibit progression of breast cancer makes it a promising therapeutic target of breast cancer . Currently, accumulating evidence suggests that breast cancer departs from a fraction of cancer initiating cells called cancer stem cells (CSCs) , which are responsible for metastasis and recurrence of the tumor. Conventional therapies fail eventually owing to not killing CSCs, which results in recurrence of tumors. To prevent breast cancer recurrence and metastasis, it will be crucial to eradicate BCSC. In a recent study, Yan et al. screened the circRNA profile in breast cancer stem cells (BCSCs) using RNA-Sequencing. 27 circRNAs were found to be aberrantly expressed of which 19 circRNAs were downregulated and 8 were upregulated. Importantly, they found that circular RNA VRK1 (circVRK1) could suppress BCSC’s expansion and self-renewal capacity. These findings indicate that circVRK1 might be a promising target for BCSCs .
Relationship between circRNA and chemoresistant breast cancer
Chemotherapy is an effective strategy for the clinical treatment of breast cancer but sometimes the efficacy of chemotherapeutics is reduced due to drug resistance, which correlates with treatment failure and poor prognosis among breast cancer patients. It is vital to understand the molecular pathways involved in the pathogenesis of breast cancer that cause metastasis and chemotherapy resistance. For example, Adriamycin (ADM) treatment is facing the challenging. Gao et al.  detected 3093 circRNAs and identified 18 circRNAs that were differentially expressed in ADMresistant MCF-7 human breast cancer cells (MCF-7/ADM) compared with parental MCF-7 cells. Importantly, a higher expression level of hsa_circ_00006528 was observed in the ADM-resistant cell lines and tissues than in the ADM-sensitive groups. In addition, a regulatory role of the hsa_circ_00006528-miR-7–5p-Raf1 axis in ADM-resistant breast cancer was identified, suggesting that hsa_circ_00006528 expression is significantly associated with ADM-resistant breast cancers and demonstrate the potential function of hsa_circ_00006528 in overcoming drug resistance. In addition, Miao et al. proved that miR-130b targets PTEN to induce multidrug resistance (MDR), proliferation and apoptosis via PI3K/Akt signaling pathway . Regarding the mechanism of circRNAs, we suspected that certain circRNAs could act as sponges for hsa-miR-130b, and several target genes related to PI3K/Akt signaling pathways, participating in chemotherapeutic resistance of breast cancer. Considering certain circRNAs are associated with chemoresistant breast cancer, dynamic analysis of aberrantly expressed circRNAs in different sensitivities to a specific chemotherapy treatment is very crucial for further therapy in breast cancer.
Breast cancer therapy targeting circRNAs
It has been shown that certain circRNAs are involved in various biological processes of breast cancer, including proliferation, migration, invasion, and apoptosis. Hence, Therapeutic strategies targeting circRNAs is expected to provide a new viewpoint for breast cancer therapy. Currently, several technologies offer an unprecedented opportunity for partial or complete removal of oncogenic circRNA, including siRNA-based therapy , anti-sense oligonucleotides therapy , CRISPER/Cas system  and so on. On the contrary, previously researches suggest that miRNAs involved in cancer can be divided into oncomiRs and tumor suppressor miRNAs. OncomiRs, as harmful miRNAs, could be countered by circRNAs via the function of miRNA sponges or other pathways. Since certain circRNA has many binding sites for a specific miRNA, it is more effective than typical miRNA inhibitors. The permuted intron-exon (PIE) method is a promising methodology for producing circRNA drugs . Such synthetic circRNA inhibitors might be future targets for therapies of breast cancer . How to deliver circRNAs efficiently to the accurate action site? Previous studies present that extracellular vesicles (EVs) are likely to be engineered to deliver circRNAs efficiently to a target tissue .
Online circRNA databases and webtools
A comprehensive database for public circRNA datasets
A knowledgebase of human circRNAs associated with diseases or traits
A database of circular RNAs derived from transcriptome sequencing data
Exploring circRNAs and their interaction with proteins or miRNAs, as well as primer design and siRNA design
Annotating alternative back-splicing and alternative splicing in circRNAs
A comprehensive database for human circular RNAs with protein-coding annotations a database for cancer-specific
A database of tissue-specific
circular RNAs in the human and mouse genomes
CircRNAs, which were thought to be errors in RNA splicing, are now regarded as an emerging key player with intriguing molecular functions in the RNA world. The abundant and stable class of RNA molecules with a range of functions, including sponge, regulation molecules, translation, biomarker and tumor suppressor are regarded as vital regulators of various physiological and pathophysiological processes. Recently, many studies have explored the clinical values of circRNAs in cancers. As summarized in this review, circRNAs are involved in various biological processes of breast cancer, including proliferation, migration, invasion, and apoptosis. As promising biomarkers in breast cancer diagnosis, prognosis, recurrence and risk evaluation, circRNAs are potential therapeutic targets. In conclusion, circRNAs provide a new perspective for the diagnosis and treatment of breast cancer. Nevertheless, compared with coding RNA and miRNA and lncRNA, there are still significant gaps in our current understanding of circRNAs and we are still far being able to incorporate circRNA into clinical practice. Here are some recommendations for future research of circRNAs in breast cancer. First, despite a growing number of papers on circRNAs have been published, conclusive answers about the precise mechanisms of circRNA underlying the initiation and progression of cancer are worth an indepth study. Second, currently the detection of circRNA in cancer mainly focus on tissue samples which is invasive and experience. Non-invasive clinical samples (blood, urine, saliva, etc.) and samples related to the disease (gastric juice, cerebrospinal fluid, etc.) should be tested for circRNA expression in the future research. Third, certain circRNAs have been verified as potential diagnostic and prognosis biomarkers but their precesion need further research. Combined detection including the combined of different circRNAs and the combined of circRNAs and traditional biomarkers deserved to be considered. Fourth, considering the important roles of circRNAs as potential targets for cancer therapy, how to deliver circRNAs efficiently to the accurate action site with a long-term sustained effect and without immunological rejection are imperatively to be studied. Fifth, since the ultimate goal of circRNA-related studies is applying cancer specific circRNAs to human diseases safely, more controlled clinical studies comprising a large number of patients are required beforehand.
With the development of research methods for identifying and validating novel circRNAs and the help of online public databases, we believe that one day, the appropriate and precise use of circRNAs in clinical diagnosis and treatment will bring tremendous progress for cancer therapy.
This work was supported by the Shanghai Municipal Health Bureau (201640097) and the Shanghai Municipal Science and Technology Commission (17411967200).
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WXH collected the related paper, drafted and revised the manuscript. Fl participated in the design of the review and helped to draft and revise the manuscript. All authors read and approved the final manuscript.
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