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Page 2 of 13 Zhang et al. Cancer Drug Resist 2024;7:30 https://dx.doi.org/10.20517/cdr.2024.62

INTRODUCTION
Breast cancer (BC) is the most common cancer in women worldwide and the leading cause of cancer-
[1]
related death. In 2022, nearly 2.3 million new cases of BC were diagnosed globally . There are many factors
that affect the incidence of BC, including age, early menarche, late menopause, hormone-replacement
therapy, lifestyle factors (e.g., alcohol intake and physical inactivity), BRCA1 and BRCA2 mutations, and so
on. The signaling pathways recognized to be involved in BC are steroid hormone signaling, human
epidermal growth factor receptor 2 (HER2/ERBB2) signaling pathway, cyclin D1/cyclin-dependent kinase
4/6/retinoblastoma protein (cyclin D1/CDK4/6/RB1), phosphatidylinositol 3-kinase/protein kinase B
(PI3K-AKT) pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and progranulin
[2-4]
(PGRN) signaling pathway . Based on the expression of estrogen receptor (ER), progesterone receptor
(PR), and HER2, BC is categorized into four molecular subtypes: Luminal A, Luminal B, HER2-positive,
[2]
and triple-negative . With the wide availability of mammography screening and targeted treatment of
different molecular subtypes, the survival rate of BC patients has significantly improved over the past two
decades. Unfortunately, the classic parameters currently used to guide treatment decisions remain
imperfect, especially in advanced cancers, which eventually develop drug resistance. Therefore, it is urgent
to find biomarkers for early detection of BC and prediction of response to treatment, thereby improving the
selection of optimized treatment.

miRNAs are 19-24-nucleotide-long non-coding RNAs (ncRNAs) that are processed from hairpin
[5]
precursors . These small non-coding RNAs (snRNAs) are pivotal in regulating gene expression by
operating at the post-transcriptional level to impact protein synthesis . They mediate the silencing process
[6,7]
[8]
of approximately 30% of coding genes after transcription . miRNAs widely participate in regulating
important biological processes such as proliferation, apoptosis, differentiation, immune response, and
maintenance of cell or tissue specificity [9,10] . miRNAs can be used as biomarkers for cancer diagnosis and the
prediction of curative effects [11,12] .

circRNAs, a subclass of ncRNAs, constitute a covalently closed circular structure in eukaryotes. They are
transcribed from protein-coding genes and undergo an unconventional precursor messenger RNA
(pre-mRNA) splicing process known as back splicing. This intricate mechanism involves the ligation of the
3’-end of an exon to the 5’-end donor splice site of the same exon or an upstream exon . Structurally,
[13]
circRNAs, originating from diverse biogenesis pathways, can be categorized into circularized intronic,
exon-intronic, exonic, and transfer RNA (tRNA) intronic subtypes . During circRNA biogenesis, distant
[14]
donor and acceptor splice sites must be brought close to facilitate ligation, culminating in the formation of a
circular structure. This process is orchestrated by various mechanisms . Several studies have shown that
[15]
circRNA affects the progression of BC [16-18] .

This review highlights the latest discoveries related to circRNAs and miRNAs associated with BC,
emphasizing their potential as biomarkers for clinical diagnosis, prognosis, and response to chemotherapy.
By comprehensively exploring the roles of circRNAs and miRNAs in BC, we aim to deepen our
understanding of this disease and provide insights for improving diagnostic and therapeutic strategies.

BIOGENESIS AND FUNCTIONAL MECHANISM OF MIRNAS AND CIRCRNAS
miRNA molecule belongs to a kind of snRNA encoded by eukaryotic genomic DNA, which is evolutionarily
highly conserved. The biosynthesis of miRNA is catalyzed by multiple enzymes in different cell
compartments, which is a complicated process. Initially, miRNA is transcribed from DNA into primary
miRNA (pri-miRNA) transcripts by RNA polymerase II or III in the cell nucleus. Afterwards, pri-miRNA
undergoes cleavage by the microprocessor complex, comprising RNAse III Drosha and its cofactor