Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Mar 11:9:647736.
doi: 10.3389/fcell.2021.647736. eCollection 2021.

Circular RNAs: Their Role in the Pathogenesis and Orchestration of Breast Cancer

Xiao He  1 , Tao Xu  2 , Weijie Hu  1 , Yufang Tan  1 , Dawei Wang  1 , Yichen Wang  1 , Chongru Zhao  1 , Yi Yi  1 , Mingchen Xiong  1 , Wenchang Lv  1 , Min Wu  1 , Xingrui Li  2 , Yiping Wu  1 , Qi Zhang  1
Affiliations
Review

Circular RNAs: Their Role in the Pathogenesis and Orchestration of Breast Cancer

Xiao He et al. Front Cell Dev Biol. .

Abstract

As one of the most frequently occurring malignancies in women, breast cancer (BC) is still an enormous threat to women all over the world. The high mortality rates in BC patients are associated with BC recurrence, metastatic progression to distant organs, and therapeutic resistance. Circular RNAs (circRNAs), belonging to the non-coding RNAs (ncRNAs), are connected end to end to form covalently closed single-chain circular molecules. CircRNAs are widely found in different species and a variety of human cells, with the features of diversity, evolutionary conservation, stability, and specificity. CircRNAs are emerging important participators in multiple diseases, including cardiovascular disease, inflammation, and cancer. Recent studies have shown that circRNAs are involved in BC progress by regulating gene expression at the transcriptional or post-transcriptional level via binding to miRNAs then inhibiting their function, suggesting that circRNAs may be potential targets for early diagnosis, treatment, and prognosis of BC. Herein, in this article, we have reviewed and summarized the current studies about the biogenesis, features, and functions of circRNAs. More importantly, we emphatically elucidate the pivotal functions and mechanisms of circRNAs in BC growth, metastasis, diagnosis, and drug resistance. Deciphering the complex networks, especially the circRNA-miRNA target gene axis, will endow huge potentials in developing therapeutic strategies for combating BC.

Keywords: breast cancer; circular RNA; diagnosis; drug resistance; metastasis; microRNA sponge.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
CircRNA formation pattern. (A) Variable cyclization mode: circRNA formation is a variable cyclization mode to generate different types of circRNAs according to different splice sites. (B) Exon skipping: the pre-mRNA is partially folded during the transcription process, so that the 3′-SD of the downstream exon is connected to the 5′-SA of the upstream exon, causing the exon to skip and form an RNA lariat containing both exons and introns. (C) Direct back-splicing: direct back-splicing is the main form of ecircRNA and EIciRNA production, where the flanking intron complementary sequences of pre-mRNAs form a lasso by direct base pairing. (D) RBP-dependent circRNA formation: RBPs bind to the sequence motifs of upstream and downstream in introns on both sides of the exon and act as the bridge to draw the distance between the flanking introns to form circRNA. (E) CiRNA formation pattern: the pre-mRNA can be spliced into an RNA lasso containing a 2′,5′-phosphodiester, resulted in the formation of ciRNAs after cutting off the 3′-tail. (F) Intergenic circRNA formation pattern: the circRNA contains two intronic circRNA fragments flanked by GT-AG splicing signals, acting as the splice donor and splice acceptor of the circular junction to finally form an intergenic circRNA. Abbreviations: circRNA, circular RNA; ecircRNA, exonic circRNA; EIciRNA, exon-intronic circRNA; RBP, RNA-binding protein; ciRNA, circular intronic RNA.
Figure 2
Figure 2
Function classification of circRNAs. CircRNAs are omnipresent in eukaryotic cells, and their functions include acting as the ceRNAs, binding to the RBP, regulating transcription, participating in translation, and forming pseudogenes, thus participating in the process of BC. BC, breast cancer; circRNA, circular RNA; RBP, RNA-binding protein.
Figure 3
Figure 3
The promoting or inhibiting impacts of differentially expressed circRNAs on the growth, metastasis, and drug resistance of BC. CircRNAs are known to function either as oncogenic or anticancer genes in BC tumor growth and metastasis, promoting BC cell-level metastasis and even the metastasis to the lung, liver, and brain. Currently, chemotherapy plays an indispensable role in the therapy of BC. However, in the process of chemotherapy, patients are prone to drug resistance which hinders the treatment progress. ADM, TAM, and monastrol are the most reported resistant drugs associated with circRNAs in recent studies in the chemotherapy of BC patients. BC, breast cancer; circRNA, circular RNA; ADM, adriamycin; TAM, tamoxifen.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Barrett S. P., Salzman J. (2016). Circular RNAs: analysis, expression and potential functions. Development 143, 1838–1847. 10.1242/dev.128074 - DOI - PMC - PubMed
    1. Braicu C., Zimta A.-A., Harangus A., Iurca I., Irimie A., Coza O., et al. . (2019). The function of non-coding RNAs in lung cancer tumorigenesis. Cancers (Basel). 11:605. 10.3390/cancers11050605 - DOI - PMC - PubMed
    1. Cai F., Fu W., Tang L., Tang J., Sun J., Fu G., et al. . (2020). Hsa_circ_0000515 is a novel circular RNA implicated in the development of breast cancer through its regulation of the microRNA-296-5p/CXCL10 axis. FEBS J. 283, 861–883. 10.1111/febs.15373 - DOI - PubMed
    1. Cao L., Wang M., Dong Y., Xu B., Chen J., Ding Y., et al. . (2020). Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1α/HK2. Cell Death Dis. 11:145. 10.1038/s41419-020-2336-0 - DOI - PMC - PubMed
    1. Chao C. W., Chan D. C., Kuo A., Leder P. (1998). The mouse formin (Fmn) gene: abundant circular RNA transcripts and gene-targeted deletion analysis. Mol. Med. 4, 614–628. 10.1007/BF03401761 - DOI - PMC - PubMed