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Published on: August 23, 2024
Targeting miR-21 to Overcome P-glycoprotein Drug Efflux in Doxorubicin-Resistant 4T1 Breast Cancer
Eun Hye Kim1,2, Youngri Ryu1,2, Jiwoong Choi1
1Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
Abstract:
Acquired resistance to chemotherapy is a major challenge in the treatment of triple-negative breast cancer (TNBC). Despite accumulated evidence showing microRNA-21 (miR-21) as a vital regulator of tumor progression, the role of miR-21 in modulating the multidrug resistance of TNBC remains obscure. In this study, we demonstrate that miR-21 affects chemoresistance in 4T1 TNBC cells in response to doxorubicin (DOX) by regulating the P-glycoprotein (P-gp) drug efflux pump. Overexpression of miR-21 in the 4T1 cells markedly reduced their sensitivity to DOX, impeding DOX-promoted cell death. We employed anti-miR-21 oligonucleotide conjugated with a PD-L1-binding peptide (P21) for targeted delivery to 4T1 tumor cells. The selective down-regulation of miR-21 in 4T1 TNBC led to the reversal of P-gp-mediated DOX resistance by up-regulating phosphatase and tensin homolog (PTEN). Our study highlights that miR-21 is a key regulator of drug efflux pumps in TNBC, and targeting miR-21 could enhance DOX sensitivity, offering a potential therapeutic option for patients with DOX-resistant TNBC.
Insights
MicroRNA-21 (miR-21) drives doxorubicin resistance in triple-negative breast cancer (TNBC) by regulating P-glycoprotein. Targeting miR-21 with a novel peptide conjugate reversed this resistance, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Acquired chemotherapy resistance is a significant hurdle in treating triple-negative breast cancer (TNBC).
- MicroRNA-21 (miR-21) is implicated in tumor progression, but its role in TNBC multidrug resistance is not fully understood.
- P-glycoprotein (P-gp) is a key drug efflux pump contributing to multidrug resistance.
Purpose of the Study:
- To investigate the role of miR-21 in doxorubicin (DOX) resistance in TNBC.
- To explore the potential of targeting miR-21 to overcome DOX resistance in TNBC.
- To elucidate the mechanism by which miR-21 affects chemoresistance in TNBC.
Main Methods:
- Utilized 4T1 TNBC cell line to study chemoresistance.
- Investigated the effect of miR-21 overexpression on DOX sensitivity.
- Employed anti-miR-21 oligonucleotide conjugated with a PD-L1-binding peptide (P21) for targeted delivery.
- Assessed the regulation of P-gp and phosphatase and tensin homolog (PTEN) by miR-21.
Main Results:
- Overexpression of miR-21 reduced 4T1 cell sensitivity to DOX and impeded DOX-induced cell death.
- Targeted delivery of anti-miR-21 (P21) selectively down-regulated miR-21 in 4T1 TNBC cells.
- Down-regulation of miR-21 reversed P-gp-mediated DOX resistance by up-regulating PTEN.
- miR-21 directly influences the P-gp drug efflux pump in TNBC.
Conclusions:
- miR-21 is a critical regulator of drug efflux pumps in TNBC.
- Targeting miR-21 can enhance DOX sensitivity in TNBC.
- This approach presents a potential therapeutic strategy for patients with DOX-resistant TNBC.
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