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

THE ROLE OF CIRCULAR RNA IN TNBC PROGRESSION
The effect of circRNA in TNBC proliferation, metastasis and invasion
Circular RNAs have a crucial role in the malignant progression of TNBC, including cell proliferation,
metastasis, and invasion. The common metastases of TNBC include brain, liver, lung, and bone metastasis,
which ultimately leads to a high mortality rate due to the presence of lesion metastasis in different parts and
degrees. Many circRNAs are highly expressed in TNBC, such as circRRM2 , circ0000851 , circEZH2 ,
[82]
[80]
[81]
circ0042881 , and circZFAND6 [Table 1]. A majority of them can enhance the miRNA sponge function,
[83]
[84]
thus promoting the proliferation, migration, and invasion ability of TNBC, including circ0000851/
[82]
[48]
[83]
[84]
miR-1183 , circEZH2/miR-217-5p , circ0042881/miR-217 , and circZFAND6/miR-647 , thereby
increasing tumor growth. In addition, a small portion of them can play a role in promoting tumor growth
by encoding or binding proteins, including circCAPG/CAPG-171aa , circEIF6/EIF6-224aa ,
[76]
[77]
[70]
[73]
[71]
circKIF4A/EIF4A3 , CircSNX25/COPB1 , and circEIF3H/IGF2BP2 . There are also some circRNAs
whose expression levels were low in TNBC, such as CircPTK2 , CircNR3C2 , circFBXW7 ,
[11]
[51]
[58]
[85]
[86]
circRNF10 , and circCCDC85A . Overexpressing these circRNAs greatly reduces the ability of TNBC
cells to grow and vice versa.
The role of circRNA in TNBC metabolism
Tumor experts consider metabolic reprogramming as one of the six fundamental hallmarks of tumor
[88]
progression . New research indicates that circRNA also plays a crucial function in tumor metabolism .
[87]
Currently, there is considerable research on the role of circRNA in TNBC metabolism, mainly focusing on
[89]
glucose metabolism . Circ-PDCD11 has been found to promote the progression of TNBC by enhancing
[55]
aerobic glycolysis . In addition, circ_0039960 is upregulated in TNBC cells, and knockdown of
circ_0039960 significantly inhibits lactate production and glucose uptake, hinders the glycolytic process, and
thus inhibits the progression of TNBC . Many enzymes involved in glucose metabolism are regulated by
[90]
circRNAs, such as hexokinase2 (HK2) and lactate dehydrogenase A (LDHA). Dou et al. reported that
circ_0008039 was upregulated in TNBC tissue and cells, and knockdown of circ_0008039 inhibited TNBC
cell proliferation, migration, invasion, and glycolysis. Western blotting demonstrated that knockdown of
circ_0008039 can decrease the expression level of HK2, which was a key rate-limiting enzyme of
glycolysis . CircRNF20 also regulates glycolysis by affecting HK2 . Circ-CSNK1G1 regulates the
[91]
[92]
glycolysis level of TNBC by acting on lactate dehydrogenase (LDH) through miR-28-5p . Besides, circRNA
[47]
derived from Myc promotes the progression of TNBC by reprogramming fatty acid metabolism. However,
there is currently relatively little research on circRNA in lipid metabolism and others. A future advance is
anticipated in our understanding of these topics.
The effect of circRNA in TNBC drug resistance
Currently, the primary method of treating TNBC in clinical settings involves chemotherapy, including
doxorubicin, albumin paclitaxel, docetaxel, and platinum. Chemotherapy is the preferred option for TNBC
and has benefited many TNBC patients. However, with the deepening of treatment, many patients have
developed certain resistance to chemotherapy drugs, so their clinical use is still limited . Chemo-resistant
[93]
TNBC is a diverse and genetically unstable condition that presents a significant challenge to the application
of personalized treatments . Research has shown that circRNA plays an important role in drug
[94]
resistance [95,96] , such as circ_0000199. It plays a role in TNBC chemo-resistance through the AKT3/miRNA
pathway. This work validates the circ_ 0000199 resistance to four chemotherapy drugs, including cisplatin,
adriamycin, paclitaxel, and gemcitabine. The MiR-206/miR-613 inhibitor blocked the negative effects of
si-hsa_circ_0000199 on PI3K/Akt/mTOR signaling and the ability of TNBC cells to respond effectively to
chemotherapy . CircWAC is a circRNA that induces TNBC PTX resistance. It acted as a miR-142 sponge
[62]
to control the PI3K/AKT signaling of TNBC cells and influence their chemosensitivity by reducing the
[57]
repressive effect of miR-142 on its target WWP1 . Wang et al. found that circCREIT was downregulated in