https://orcid.org/0009-0003-2122-541X
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Abstract
Triple-negative breast cancer (TNBC) has negative expressions of ER, PR and HER2. Due to the insensitivity to both endocrine therapy and HER2-targeted therapy, the main treatment method for TNBC is cytotoxic chemotherapy. However, the curative effect of chemotherapy is limited because of the existence of acquired or intrinsic multidrug resistance. MicroRNAs (miRNAs) are frequently dysregulated in malignant tumors and involved in tumor occurrence and progression. Interestingly, growing studies show that miRNAs are involved in chemoresistance in TNBC. Thus, targeting dysregulated miRNAs could be a plausible way for better treatment of TNBC. Here, we present the updated knowledge of miRNAs associated with chemoresistance in TNBC, which may be helpful for the early diagnosis, prognosis and treatment of this life-threatening disease.
Plain language summary
Triple-negative breast cancer (TNBC) is a subtype of breast cancer, which is characterized by high rates of invasion, recurrence and distant metastasis. At present, chemotherapy is still the main treatment option for TNBC. However, after some time, the sensitivity of tumor cells to chemotherapeutic drugs gradually decreases, which makes tumor cells develop chemoresistance. MicroRNAs (miRNAs) are a class of small RNA molecules with length of 19–25 nucleotides that do not encode proteins. The expression level of miRNAs in cancer is usually abnormal. More and more studies have shown that miRNAs are involved in cancer development and associated with drug resistance. Therefore, this review summarizes the miRNAs associated with chemoresistance in TNBC.
Tweetable abstract
Review discussing the role of microRNAs in the development of chemoresistance in TNBC to indicate that they could be therapeutic targets and improve the chemosensitivity of TNBC.
Background
Triple-negative breast cancer (TNBC) is one breast cancer subtype characterized by lack of PR, ER and HER2 expressions.
Due to the absence of ER, PR and HER2, the application of endocrine therapy and anti-HER2-targeted therapy in TNBC is limited.
At present, chemotherapy is still the main treatment option for TNBC, but it is easy to produce chemoresistance, which is the main cause of chemotherapy failure.
MiRNAs involved in chemoresistance in TNBC
MiRNAs can bind to the 3′-UTR of target mRNAs and then regulate their expression level.
As oncogenes or tumor suppressors, miRNAs not only are involved in basic biological processes, including proliferation, migration, invasion and apoptosis, but also play a key role in chemoresistance.
MiRNAs involved in drug efflux
Drug transporters can transport anti-cancer drugs out of tumor cells, reducing the accumulation of drugs and causing drug resistance in tumor cells.
Some miRNAs could regulate drug efflux and thus participate in chemoresistance of TNBC.
MiRNAs involved in apoptosis
The evasion of apoptosis confers chemoresistance to some cytotoxic drugs.
MiRNAs could regulate apoptosis-related factors and thus regulate drug resistance in TNBC.
MiRNAs involved in epithelial–mesenchymal transition
Epithelial–mesenchymal transition (EMT) can be regulated by miRNAs and participate in some processes of cancer occurrence and development as well as chemoresistance.
MiRNAs involved in genomic instability
Genomic instability (GIN) is the key to tumor development and tumor chemoresistance, among which DNA damage response is a vital biological process to maintain the genome stability.
MiRNAs could regulate DNA damage response and thus affect chemoresistance.
MiRNAs involved in specific signaling pathways
Some signaling pathways are related to the chemoresistance of tumor cells, such as Wnt/β-catenin, Notch, TGF-β, ERK, and PI3K/AKT/mTOR signaling pathway.
MiRNAs regulate the development of drug resistance in TNBC via the participation in modulating various signaling pathways.
Other mechanisms of chemoresistance in TNBC
MiRNAs are associated with most of the mechanisms of chemoresistance in TNBC.
No studies show that miRNAs are related to other mechanisms of chemoresistance, such as CSCs induction after NAC, hypoxia and Hedgehog signaling pathway.
Conclusion
MiRNAs can regulate their target genes and then participate in drug resistance of TNBC.
MiRNAs have the potential therapeutic value in gene therapy strategy.
Specific miRNAs are promising to become biomarkers for diagnosis and possible therapeutic targets for TNBC.
Controlling the expression level of cancer-associated miRNAs is a novel treatment strategy for TNBC.
Future perspective
Clinical trials of miRNA inhibitors or mimics that can treat TNBC or improve drug sensitivity of TNBC may be a future research direction.
Author contributions
Writing-original draft preparation, L-J Yan, ATY Lau and Y-M Xu; writing-review and editing, L-J Yan, ATY Lau and Y-M Xu; supervision, ATY Lau and Y-M Xu.; funding acquisition, ATY Lau and Y-M Xu. All authors read and agreed to the published version of the manuscript.
Financial disclosure
This work was supported by the grants from the National Natural Science Foundation of China (31771582 and 31271445), the Guangdong Natural Science Foundation of China (2017A030313131), the “Thousand, Hundred, and Ten” Project of the Department of Education of Guangdong Province of China, the Basic and Applied Research Major Projects of Guangdong Province of China (2017KZDXM035 and 2018KZDXM036), the “Yang Fan” Project of Guangdong Province of China (Andy T. Y. Lau-2016; Yan-Ming Xu-2015), and the Shantou Medical Health Science and Technology Plan (200624165260857).
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Acknowledgments
The authors would like to thank members of the Lau and Xu laboratory for critical reading of this manuscript.