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Page 2 of 14 Xu et al. Cancer Drug Resist 2024;7:13 https://dx.doi.org/10.20517/cdr.2023.141

INTRODUCTION
The latest research report indicates that breast cancer is now the most prevalent form of cancer in the world,
[1]
with the highest incidence among all major cancers . According to its histological characteristics and
expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor
receptor 2 (HER2), breast cancer can be subdivided into luminal A, luminal B, HER2 overexpression, and
[2,3]
[4]
triple-negative breast cancer (TNBC), respectively . The incidence of TNBC ranges from 15% to 20% and
it is difficult to identify the potential therapeutic targets. Thus, it leads to an increased risk of recurrence and
metastasis and the patients have poor prognosis and shorter overall survival . Investigation into the
[5]
detailed molecular pathogenesis of TNBC and the development of potential therapeutic targets are
important tasks in order to improve the prognosis more effectively and prolong the survival time of TNBC
patients.

Circular RNAs (circRNAs) have recently gained significant attention as they are involved in various
diseases, including human cancers such as TNBC. Many studies suggested that circRNAs are strongly
[6]
associated with the occurrence and development of tumors. They are non-coding RNAs that have been
recently discovered and are formed by reverse splicing the precursor messenger RNAs (mRNAs).
Compared with linear RNA, circRNAs do not have a 5 'end cap and a 3' end polyA tail which is more stable
[7,8]
and not easily degraded by nuclease . Its main functions include microRNA (miRNA) sponging , RNA
[9]
binding protein (RBP) binding , and serving as a translation template . Studies have indicated that
[10]
[11]
circRNAs have the capability to regulate downstream genes and contribute to tumor proliferation, invasion,
and metastasis. Therefore, identifying the specific role that circRNAs play in tumor development and
occurrence is of great importance.
[12]
The first discovery of circRNA in eukaryotic cells was made through electron microscopy in 1979 .
However, due to the scientific limitations at that time, circRNA was considered as a product of abnormal
splicing events . With the advancement of next-generation sequencing technology and bioinformatic
[13]
analysis tools, a large number of circRNAs have been identified in eukaryotic genome and transcriptome .
[14]
This identification implies that circRNAs are not accidental by-products, but normal components of the
body that are widely expressed in eukaryotes, including humans . Therefore, scientists began to conduct
[15]
detailed research on various functions served by circRNAs. Recently, an increasing number of circRNAs
have been reported to be differentially expressed in breast cancer. These aberrantly expressed circRNAs
mediate a range of tumorigenic processes, including cell proliferation, metastasis, apoptosis, and cell
[16]
metabolism . Hence, we summarized current information on abnormal expression of specific circRNAs
that are implicated in TNBC development, followed by current clinical applications and potential
therapeutic utility of circRNAs. It is clear that circRNA holds promise as a future therapeutic target .
[17]

FORMATION AND TYPES OF CIRCRNAS
The mechanism for circRNA formation is still not clear. It is generally accepted that they are derived from
precursor mRNAs (pre-mRNAs), which are closed-loop molecules formed by back splicing . Depending
[8]
on their composition and synthetic mechanism, circRNAs can be categorized into three main groups:
EciRNA, EIciRNA, and ciRNA . First, EciRNAs are derived entirely from the exons of parental genes. In
[18]
the process of forming EciRNA, a splice donor downstream of the 5' splice site is attached to a splice
acceptor upstream of the 3' splice site, which is called back-splicing . This molecular event produces a
[15]
circular format of RNA with a 3'-5' phosphodiester bond at the back-splicing junction (BSJ) site. EciRNA is
the most common type of circRNA and is mainly located in the cytoplasm . Depending on the distribution
[19]
of specific organelles, these circRNAs in the cytoplasm perform different functions. Second, EIciRNAs are
circRNAs resulting from the retention of introns located in the 5' donor and the 3' acceptor on the