Page 71 - Read Online

Page 8 of 13 Zhang et al. Cancer Drug Resist 2024;7:30 https://dx.doi.org/10.20517/cdr.2024.62

BC is composed of heterogeneous cell populations, which are mainly divided into two types of cell
[58]
populations: BC stem cells (BCSC) and differentiated cells . EMT is the most important pathway involved
in BCSC phenotypic regulation. EMT is characterized by the loss of epithelial phenotype and the gain of
mesenchymal characteristics, and it is a key factor for the development of resistance to multiple
chemotherapeutic drugs. In recent years, more and more reports have shown that miRNAs and circRNAs
are involved in drug resistance by regulating EMT and stem cell properties. Research found that
miR-708-3p inhibits EMT and metastasis while increasing sensitivity to doxorubicin both in vitro and
in vivo, by directly targeting EMT activators such as vimentin, cadherin-2 (CDH2), and zinc finger E-box
binding homeobox 1 (ZEB1) . Downregulation of miR-873 was shown to increase the mesenchymal
[73]
[74]
phenotype by elevating ZEB1 expression, thereby promoting gemcitabine resistance in TNBC . In
addition, circ-PVT1 increased EMT and promoted paclitaxel resistance by inducing the expression of the
regulator ZEB1 through miR-124-3p . Therefore, EMT-inducing regulators including miRNAs and
[75]
circRNAs may become useful therapeutic strategies to address drug resistance.

MIRNAS, CIRCRNAS, AND RESPONSE TO ENDOCRINE THERAPY IN BC
Endocrine therapy is one of the commonly used treatments for BC patients and is suitable for hormone
receptor-positive BC patients [76-78] . However, there are significant differences in the response of various
patients to endocrine therapy. Recent studies have indicated that the expression of miRNA and circRNA
may be closely associated with the response of BC patients to endocrine therapy. Some miRNAs and
circRNAs were found to be correlated with the expression levels of endocrine receptors (ER and PR), which
play a crucial role in endocrine therapy. miR-342 expression was positively correlated with ERα mRNA in
tissue samples, and its introduction into ER-dependent cells enhanced BC sensitivity to tamoxifen .
[79]
[80]
circPVT1 promotes the expression of ESR1 and ERα through miR-181a-2-3p . Antisense oligonucleotides
(ASOs) targeting circPVT1 inhibited the growth of ERα-positive BC cells and tumors and sensitized
tamoxifen-resistant ERα-positive BC cells to tamoxifen treatment. In addition, some miRNAs and circRNAs
may also affect the sensitivity of BC cells to hormones by regulating signaling pathways or target genes
related to endocrine therapy. miR-519a is a novel oncogenic miR in ER-positive BC cells that enhances cell
viability, promotes cell cycle progression, and confers resistance to tamoxifen-induced apoptosis .
[81]
miR-125a-3p is downregulated in tamoxifen-resistant BC cells. It targets cell cycle-dependent kinase 3 both
in vivo and in vitro and inhibits the transcriptional activity of ERα, thereby inhibiting the proliferation of
ER-positive BC cells. This leads to cell cycle arrest in G1/S phase, induction of apoptosis, and inhibition of
[82]
tumor growth . CircRNA_0044556 reduces the sensitivity of TNBC cells to ADM through the
miR-145/NRAS axis . Through an in-depth investigation of the mechanisms of action of miRNA and
[83]
circRNA in endocrine therapy, we hope to identify new biomarkers for predicting the response of BC
patients to endocrine therapy and provide a basis for personalized treatment. These research findings may
contribute to improving the treatment outcomes of BC patients, reducing unnecessary treatments, and
promoting the development of personalized and precision medicine in BC therapy.

MIRNAS, CIRCRNAS, AND RESPONSE TO TARGETED THERAPY IN BC
Targeted therapy is a cancer treatment method that targets specific genes or proteins. Trastuzumab is the
first humanized mAb developed for HER2 and has achieved remarkable success in the treatment of HER2-
positive BC . However, it has been observed that some BC patients are insensitive to HER2 treatment or
[84]
change from susceptible to resistant. Increased expression of miR-221 can be observed in trastuzumab-
resistant cells . Circ-BGN is overexpressed in trastuzumab-resistant BC tissues, and its downregulation
[85]
reduces cell viability, especially restoring sensitivity to trastuzumab . These findings indicate that the
[86]
expression of miRNA and circRNA has an impact on the efficacy of trastuzumab. In addition,
overexpression of circCDYL2 stabilized growth factor receptor-bound protein 7 (GRB7) by preventing its