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Engineered EVs-Mediated miR-222 Targeting PTEN/FN1 Axis Reverses Anthracycline Resistance in HER2-Negative Breast
Sujin Yang1,2, Mei Yang3, Quanfeng Shao3
1Department of Breast Surgery, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China.
Abstract:
Anthracycline resistance represents a critical therapeutic challenge in breast cancer treatment, wherein alterations in the tumor immune microenvironment and enhanced cellular resistance mechanisms facilitate chemoresistance progression. Transcriptome analysis of 142 HER2-negative breast cancer patients undergoing anthracycline-based chemotherapy revealed four distinct tumor-infiltrating cell subtypes, with subtype D exhibiting elevated M1 macrophage infiltration and superior prognostic outcomes. Differential expression analysis identified miR-222 as the predominantly upregulated microRNA in adriamycin-resistant cells, while Tandem Mass Tag mass spectrometry-based quantitative analysis elucidated PTEN as its direct target and FN1 as a crucial downstream mediator. Engineered extracellular vesicles (EVs) carrying a miR-222 inhibitor were developed to reverse adriamycin resistance via PTEN/FN1 signaling modulation. Molecular docking analysis found specific PTEN-FN1 protein interactions characterized by stable hydrogen bonds at ARG142-ASP23 and ARG15-GLU95. In xenograft models, EVs-mediated delivery of the miR-222 inhibitor significantly attenuated MCF-7/ADR tumor progression through miR-222 suppression and PTEN restoration, with concordant molecular alterations observed in serum-derived EVs. Our findings establish a novel mechanism of EVs-mediated drug resistance through the microRNA-222/PTEN/FN1 axis and present Engineered EVs as a promising therapeutic strategy for anthracycline resistance in breast cancer, while highlighting circulating EVs profiles as potential treatment monitoring biomarkers.
Insights
Engineered extracellular vesicles carrying a miR-222 inhibitor can overcome anthracycline resistance in breast cancer by targeting the miR-222/PTEN/FN1 pathway, offering a new therapeutic approach.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Anthracycline resistance is a major obstacle in breast cancer treatment, driven by tumor immune microenvironment changes and cellular resistance.
- Understanding the molecular mechanisms underlying chemoresistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of microRNA-222 (miR-222) in anthracycline resistance in breast cancer.
- To explore the potential of engineered extracellular vesicles (EVs) as a delivery system to overcome drug resistance.
Main Methods:
- Transcriptome analysis of breast cancer patients to identify tumor-infiltrating cell subtypes.
- Differential expression analysis and Tandem Mass Tag (TMT) mass spectrometry to identify key molecular targets (miR-222, PTEN, FN1).
- Development of engineered EVs to deliver miR-222 inhibitors.
- Molecular docking to analyze protein interactions.
- In vivo xenograft models to evaluate therapeutic efficacy.
Main Results:
- Subtype D breast tumors showed M1 macrophage infiltration and better outcomes.
- miR-222 was upregulated in adriamycin-resistant cells, targeting PTEN and regulating FN1.
- Engineered EVs delivering miR-222 inhibitors reversed adriamycin resistance in vitro and in vivo by suppressing miR-222 and restoring PTEN.
- Specific PTEN-FN1 interactions were identified via molecular docking.
- Circulating EVs in patients showed molecular alterations consistent with treatment response.
Conclusions:
- A novel mechanism of EVs-mediated drug resistance involving the microRNA-222/PTEN/FN1 axis was established.
- Engineered EVs represent a promising therapeutic strategy for overcoming anthracycline resistance in breast cancer.
- Circulating EVs hold potential as biomarkers for monitoring treatment response.
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