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Published on: June 9, 2023
Let-7b-5p sensitizes breast cancer cells to doxorubicin through Aurora Kinase B
Murat Kaya1, Asmaa Abuaisha2, Ilknur Suer3
1Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Medical Genetics, Istanbul University, Capa, Fatih, Istanbul, Turkey.
Abstract:
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate the expression level of the target genes in the cell. Breast cancer is responsible for the majority of cancer-related deaths among women globally. It has been proven that deregulated miRNAs may play an essential role in the progression of breast cancer. It has been shown in many cancers, including breast cancer, that aberrant expression of miRNAs may be associated with drug resistance. This study investigated the effect of let-7b-5p, detected by bioinformatics methods, on Dox resistance through the Aurora Kinase B (AURKB) gene. In silico analysis using publicly available miRNA expression, GEO datasets revealed that let-7b-5p significantly downregulated in BC. Further in silico studies revealed that of the genes among the potential targets of let-7b-5p, AURKB was the most negatively correlated and may be closely associated with Dox resistance. Expression analysis via quantitative PCR confirmed that let-7b-5p was downregulated and AURKB was upregulated in breast cancer tissue samples. Later, functional studies conducted with MCF-10A, MCF-7, and MDA-MB-231 cell lines demonstrated that let-7b-5p inhibits cancer cells through AURKB and sensitizes them to Dox resistance. In conclusion, it has been shown that the let-7b-5p/AURKB axis may be significant in breast cancer progression and the disruption in this axis may contribute to the trigger of Dox resistance.
Insights
MicroRNAs (miRNAs) like let-7b-5p are downregulated in breast cancer (BC), promoting Doxorubicin resistance by upregulating Aurora Kinase B (AURKB). Restoring let-7b-5p may overcome this resistance.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- MicroRNAs (miRNAs) are key regulators of gene expression.
- Aberrant miRNA expression is implicated in breast cancer (BC) progression and drug resistance.
- Doxorubicin (Dox) resistance is a major challenge in BC treatment.
Purpose of the Study:
- To investigate the role of let-7b-5p in Doxorubicin resistance in breast cancer.
- To explore the relationship between let-7b-5p, Aurora Kinase B (AURKB), and Doxorubicin resistance.
- To determine the therapeutic potential of targeting the let-7b-5p/AURKB axis.
Main Methods:
- Bioinformatic analysis of miRNA expression and gene correlation using public datasets (GEO).
- Quantitative PCR (qPCR) to validate miRNA and gene expression in BC tissues.
- Functional studies in breast cancer cell lines (MCF-10A, MCF-7, MDA-MB-231) to assess let-7b-5p effects on cell viability and Dox sensitivity via AURKB.
Main Results:
- let-7b-5p was significantly downregulated in breast cancer tissues.
- AURKB was identified as a key target gene negatively correlated with let-7b-5p and associated with Doxorubicin resistance.
- let-7b-5p restoration inhibited cancer cell growth and sensitized cells to Doxorubicin by downregulating AURKB.
Conclusions:
- The let-7b-5p/AURKB axis plays a critical role in breast cancer progression.
- Disruption of this axis contributes to Doxorubicin resistance.
- Targeting the let-7b-5p/AURKB pathway presents a potential strategy to overcome Doxorubicin resistance in breast cancer.
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