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Page 6 of 14 Xu et al. Cancer Drug Resist 2024;7:13 https://dx.doi.org/10.20517/cdr.2023.141

protein to inhibit TNBC development by increasing FBXW7
expression
CircPLK1 High miR-296-5p PLK1 CircPLK1 may be a target of miR-296-5p for the regulation of PLK1 [65]
expression
CircKIF4A High miR-637 STAT3 CircKIF4A regulates STAT3 expression levels through miR-375 [66]
CircEPSTI1 High miR-4753 miR- BCL11A CircEPSTI1 acts as a sponge for miR-4753 and miR-6809, which [67]
6809 regulate the expression of BCL11A

TNBC: Triple-negative breast cancer; OGA: O-GlcNAcase; EGFR: epidermal growth factor receptor; THP: trastuzumab and pertuzumab in
combination with taxanes; DACT2: disheveled binding antagonist of beta-catenin 2; LDHA: lactate dehydrogenase A.

muscle protein 1. The gene produces circMBL in both Drosophila and humans, with the binding sites of
MBL and MBNL1, respectively . Similar to circMBL, other circRNAs in breast cancer also function by
[69]
connecting with their target proteins. For example, circKIF4A stabilizes the mRNA expression of SDC1 by
attaching to EIF4A, triggers the c-src/FAK signaling pathway, and leads to the advancement of disease in
TNBC . Mass spectrometry and RNA Binding Protein Immunoprecipitation experiments demonstrated
[70]
that circSNX25 binds to COPB1(Coatomer Protein Complex, Subunit Beta 1) to promote the malignant
progression of TNBC, bringing extremely poor prognosis . The above two examples of circRNAs are
[71]
intended to demonstrate their functions in binding to proteins. Additionally, circRNAs have the ability to
facilitate mRNA translation. Circ_0076611 is a circRNA produced by MALAT1-dependent production that
binds to many transcripts, including the mRNAs for MYC and VEGFA. It can affect the cell cycle and
promote cell proliferation by facilitating the binding of MYC and VEGFA mRNAs to translation initiation
factors and elevating their protein expression, leading to TNBC progression . It also functions as a protein
[72]
scaffold. For example, circEIF3H can directly combine with IGF2BP and HuR proteins to form the
circEIF3H-IGF2BP2-HuR scaffolding complex, which in turn is inextricably linked to mRNA stability. In
this case, circEIF3H promotes TNBC progression by stabilizing downstream HSPD1/RBM8A/G3BP1
mRNA expression in an indirect manner .
[73]

Encoding proteins
Recent research found that circRNA encodes proteins, which changes the traditional recognition that
6
circRNA is non-coding RNA. Either the internal ribosome entry site (IRES) or the m 5' “untranslated
[74]
region (UTR)” can be used for cell-independent translation of circRNA . The protein encoded by circRNA
[75]
can activate some downstream signal pathways to promote the occurrence of TNBC. CircFBXW7 can
sponge miR-197-3p and encode a 185-aa protein, thus inhibiting malignant progression in TNBC .
[11]
CircCAPG produces a polypeptide known as CAPG-171aa. This polypeptide promotes cancer growth by
inhibiting the binding between serine/threonine kinase 38 (STK38) and SMAD-specific E3 ubiquitin protein
ligase 1 (SMURF1), which prevents MEKK2 from undergoing ubiquitination and proteasomal
degradation . Circ-EIF6 exerts pro-oncogenic effects on TNBC through its encoded peptide EIF6-224aa,
[76]
which decreases the ubiquitinated degradation of the oncogene MYH9, thereby increasing its expression to
[77]
activate the downstream Wnt/beta-catenin signaling pathway . CircSEMA4B, which is significantly
downregulated in TNBC tissues and cell lines, encodes a novel protein called SEMA4B. Both circSEMA4B
and SEMA4B inhibit TNBC proliferation and migration in vitro and in vivo . In addition, a study has
[78]
shown that circHER2 is present in TNBC and encodes the novel protein HER2-103. This protein targets the
HER2-targeting drug Pertuzumab, which has been commonly used in clinical treatment. It was suggested
that some TNBC patients may benefit from Pertuzumab in the future . However, so far, only a few
[79]
circRNA has been found to encode proteins and the functional significance of most circRNA-derived
peptides is still unknown.