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Page 8 of 14 Xu et al. Cancer Drug Resist 2024;7:13 https://dx.doi.org/10.20517/cdr.2023.141

doxorubicin-resistant TNBC cells. Using a patient-derived organoid, they revealed that circCREIT
overexpression greatly enhanced doxorubicin sensitivity of TNBC cells and demonstrated that this function
[97]
is mainly achieved by stabilizing PKR . In addition, circNCOR1 was shown to modulate TNBC
[42]
[43]
radiotherapy resistance , and circFGFR4 was associated with TNBC immunotherapy resistance .
Although basic research has demonstrated that circRNAs play an important role in TNBC resistance,
relevant clinical trials have not yet been performed.

The effect of circRNA in TNBC immune microenvironment
Many circRNAs have been discovered in ovarian cancer , lung adenocarcinoma , colorectal cancer ,
[99]
[100]
[98]
esophageal cancer , pancreatic cancer , and oral squamous cell carcinoma in which they regulate
[103]
[101]
[102]
tumor immune microenvironment. CircRNAs can induce programmed cell death , and enhance PD-1/
[104]
PD-L1 binding by increasing PD-1 expression, preventing T cell identification and triggering, thus causing
immune escape of tumor cells. Moreover, circRNAs also regulate NK cells, macrophages, neutrophils,
myeloid-derived inhibitory cells, and cancer-associated fibroblasts through complex pathways to affect
tumor development. There are also some immune-related circRNAs in breast cancer. CircWWC3 induces
repolarization of M1 macrophages to M2 by increasing the expression of IL-4 and PD-L1 that promotes the
escape of immune cells from tumors and worsens the growth of TNBC. Breast cancer patients with high
levels of circWWC3 or PD-L1 expression and high CD163-expressing macrophages are correlated with low
overall survival (OS) and disease-free survival (DFS) . Circ_0001142 was found to be highly expressed in
[105]
BCs. It was packaged in exomes and released by endoplasmic reticulum stress which induces M1
macrophage repolarization and promotes TNBC progression through the PI3K/AKT pathway .
[106]

CircRNA and the clinical treatment of TNBC
Most tumor progression is due to a lack of early monitoring and examination of the body, and TNBC is no
exception. Early detection and treatment can greatly improve the survival rate of TNBC patients. The
structure of circRNA is stable and can be easily detected in blood, urine, saliva, and other biological tissues.
Therefore, researchers are exploring the relationship between circRNA and tumor development and
whether it can reflect the clinical prognosis of patients after treatment. Currently, many circRNAs have been
found to be associated with the prediction, treatment, and prognosis of TNBC . The relevant circRNAs
[107]
identified in TNBC in recent years are summarized in Table 2. The vast majority of the circRNAs identified
are pro-oncogenic, with elevated expression in TNBC. Only a few of them play an anti-tumor role and are
downregulated in TNBC. Recent research found that they are all related to clinicopathological
characteristics and OS or DFS. Among them, circCAPG (AUC 0.8723), circDNAJC11 (AUC 0.658),
[108]
[76]
circSEPT9 (AUC 0.711), circRAD18 (AUC 0.752), circTADA2A-E6 (AUC 08554), and
[117]
[116]
[112]
circAHNAK1 (AUC 0.72) have a role as prognostic markers for TNBC treatment. In addition, circ
[119]
0072309 can also be used as a biomarker, but there is currently no research on its relationship with
[124]
clinicopathological characteristics and survival rate. Circ_0000851 is associated with Ki-67, tumor size, and
lymph node metastasis, but the relationship to survival has yet to be elucidated . It is possible that
[81]
additional circRNAs will be discovered in the future, which could serve as prognostic markers and
promising targets for the therapy of TNBC.
CONCLUSION
Breast cancer is a major life-threatening disease for women around the world and has to be examined in
depth. As the most malignant type among them, TNBC deserves wider attention. Scientific and
technological development has led to the gradual recognition of circRNA with special properties, which has
become a popular area of research in recent years. CircRNA is widely expressed in organisms due to its
structural stability. Recent studies indicated that circRNA is not a class of by-products, but a normal
component of the body that plays an important regulatory role in a variety of diseases, including tumor.