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miR3609 sensitizes breast cancer cells to adriamycin by blocking the programmed death-ligand 1 immune checkpoint
Duolu Li1, Xinru Wang1, Meng Yang1
1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Abstract:
Chemoresistance is the leading cause of breast cancer therapy failure, and studies of the mechanisms underlying chemoresistance and the treatment of drug-resistant tumors remain challenging. In the present study, we discovered a novel microRNA, miR3609, that influences the malignancy of breast cancer. Our results showed miR-3609 expression was lower in resistant breast cancer cells than in sensitive breast cancer cells (MCF-7), while PD-L1 expression was higher in resistant breast cancer cells than in sensitive breast cancer cells. Co-transfection of a miR-3609 plasmid with a luciferase construct containing the PD-L1 3'-untranslated region suppressed luciferase activity. Transfection of a miR-3609 mimic markedly suppressed PD-L1 protein expression in MDA-MB-231 and MDA-MB-468 cells in a dose-dependent manner and increased the sensitivity of MCF7/ADR cells to adriamycin, whereas transfection of a miR-3609 inhibitor enhanced PD-L1 protein expression in HBL-100 and MCF-7 cells. In addition, knockdown of PD-L1 by siRNA restored the sensitivity of MCF7/ADR cells to adriamycin. Mice injected with breast cancer cells stably overexpressing miR3609 survived markedly longer and had fewer tumors than mice injected with control miRNA (miR-sc)-transfected cells. Treatment with a CD8+ blocking antibody (anti-CD8) eliminated these effects, suggesting that CD8+ T cells are required for the efficacy of miR3609 in breast cancer. Further, low miR-3609 expression and high PD-L1 expression were correlated with poor prognosis in breast cancer patients. Therefore, restoration of miR-3609 expression may sensitize breast cancer to adriamycin by blocking PD-L1 expression.
Insights
A novel microRNA, miR3609, was found to reduce breast cancer malignancy by targeting PD-L1. Restoring miR3609 may overcome chemoresistance and improve patient prognosis in breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Chemoresistance is a major challenge in breast cancer therapy, leading to treatment failure.
- Understanding the mechanisms of drug resistance and developing effective treatments for resistant tumors is critical.
Purpose of the Study:
- To identify novel microRNAs involved in breast cancer chemoresistance.
- To investigate the role of miR3609 in breast cancer malignancy and its potential as a therapeutic target.
Main Methods:
- Expression analysis of miR3609 and PD-L1 in sensitive and resistant breast cancer cells.
- Luciferase reporter assays to confirm the interaction between miR3609 and PD-L1.
- In vitro experiments using miR3609 mimics and inhibitors in various breast cancer cell lines.
- In vivo studies using mouse models of breast cancer.
- Analysis of patient data correlating miR3609 and PD-L1 expression with prognosis.
Main Results:
- miR3609 expression was lower, and PD-L1 expression was higher in chemoresistant breast cancer cells.
- miR3609 directly targets and suppresses PD-L1 protein expression.
- Restoring miR3609 increased adriamycin sensitivity in resistant cells and reduced tumor growth in vivo.
- The therapeutic effect of miR3609 in vivo was dependent on CD8+ T cells.
- Low miR3609 and high PD-L1 expression correlated with poor prognosis in breast cancer patients.
Conclusions:
- miR3609 acts as a tumor suppressor in breast cancer by inhibiting PD-L1.
- Restoration of miR3609 can overcome adriamycin resistance and enhance anti-tumor immunity.
- miR3609 represents a potential therapeutic strategy for chemoresistant breast cancer.
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