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Zhang et al. Cancer Drug Resist 2024;7:30 https://dx.doi.org/10.20517/cdr.2024.62 Page 3 of 13

DiGeorge syndrome critical region 8 (DGCR8), resulting in the formation of a precursor miRNA
(pre-miRNA) hairpin structure. Under the regulation of the Ras superfamily member RanGTP protein,
[19]
pre-miRNA is transported to the cytoplasm via the shuttle protein exportin 5 . Once in the cytoplasm, the
ribonuclease Dicer RNase catalyzes the cleavage of pre-miRNA into mature double-stranded miRNA with a
length of 21 to 23 nucleotides . After being processed by Dicer, the double-stranded miRNA becomes two
[20]
single strands known as the guide strand or mature miRNA. One of the two strands binds to RNA-induced
silencing complex (RISC, also referred to as miRISC), and the other strand is degraded and is known as the
star strand miRNA or passenger strand [21,22] . The binding mechanism between mature miRNA and RISC to
regulate target mRNA contains: (1) mRNA cleavage by miRNA binding site; and (2) translation inhibition.
Pairing between miRNA and typically 3’ untranslated region (3’- UTR) of target mRNA is crucial for their
[23]
interaction in animals . Each miRNA may act on multiple mRNAs, and conversely, an mRNA can be
regulated by several different miRNAs [Figure 1] [24,25] .

Circular RNA (circRNA) is a non-coding RNA characterized by a covalently closed loop structure devoid of
a 5’ cap and a 3’ polyadenylated tail. First, circRNA is transcribed from genomic DNA by RNA polymerase
II or III, similar to linear mRNA transcripts. Subsequently, during the splicing process, the downstream 5’
splice site of the precursor mRNA (pre-mRNA) is back-spliced with the upstream 3’ splice site to form a
circular molecule [26-28] . CircRNAs can significantly contribute to the progression of diverse diseases by
exerting various biological effects [29-31] . In the context of known tumor development, circRNA exhibits
multiple functions, including: (A) acting as a sponge for competing endogenous RNA (ceRNA) or miRNA;
(B) acting as sponges for RNA-binding proteins (RBPs); (C) participating in protein translation; (D)
regulating transcription and splicing; and (E) interacting with RNA-binding proteins [Figure 2] [32-36] .

MIRNAS AND CIRCRNAS AS DIAGNOSTIC MARKERS IN BC
BC is an epithelial malignancy arising from the terminal ductal lobular unit of the breast, which is generally
categorized into non-invasive or invasive carcinoma based on histology. Non-invasive carcinoma is further
divided into ductal and lobular carcinoma in situ. Invasive BC penetrates surrounding breast tissue and
primarily includes invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) . BCs in different
[2]
tissue types and molecular subtypes differ in pathology, genomic profiles, metastatic organ chemotaxis, and
responses to treatment. But in any case, early diagnosis of BC is the most effective way to reduce mortality.
Identifying biomarkers for the early detection of BC is crucial.

Since miRNAs and circRNAs control many biological events related to cancer, they are often associated
with the early diagnosis of the disease. Studies have shown that some circRNAs and miRNAs exhibit
differential expression patterns in BC compared to normal tissues, and these circRNAs and miRNAs may be
involved in the occurrence and development of BC by regulating cancer-related genes. Similarly, certain
circRNAs and miRNAs can also be detected in serum exosomes, and their expression levels may be
associated with clinical features of BC [Figure 3]. Recent research has found that five plasma miRNAs
(miR-122-5p, miR-210-3p, miR-146b-5p, let-7b-5p, and miR-215-5p) exhibited significantly different
[37]
expression levels between BC patients and normal controls . A signature comprising the five miRNAs
showed excellent discriminatory accuracy with the area under curve (AUC) values 0.683, 0.966, and 0.978
for the training, testing, and external validation sets, respectively. When combined, twelve cell-free miRNAs
showed outstanding discriminatory accuracy, achieving an AUC value of 0.95. Furthermore, the expression
of circ_0001640, circ_0001531, and circ_0000745 were upregulated in BC patients compared with benign
[38]
tumors and healthy controls. The AUC of the panel was 0.9130 . These results indicate that miRNA and
circRNA can be used as markers for the diagnosis of BC. Further studies have found that miRNAs exhibit
different expression levels in BCs of various tissue types. A comparison of miRNAs between low-grade and