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Monitoring of Nanodrug Accumulation in Murine Breast Cancer Metastases
Published on: August 23, 2024
miR-146a-5p Promotes Angiogenesis and Confers Trastuzumab Resistance in HER2+ Breast Cancer
Paula Cabello1,2, Sandra Torres-Ruiz1, Anna Adam-Artigues1
1Biomedical Research Institute INCLIVA, 46010 Valencia, Spain.
Abstract:
Trastuzumab treatment has significantly improved the prognosis of HER2-positive breast cancer patients. Despite this, resistance to therapy still remains the main clinical challenge. In order to evaluate the implication of microRNAs in the trastuzumab response, we performed a microRNA array in parental and acquired trastuzumab-resistant HER2-positive breast cancer cell lines. Our results identified miR-146a-5p as the main dysregulated microRNA. Interestingly, high miR-146a-5p expression in primary tumor tissue significantly correlated with shorter disease-free survival in HER2-positive breast cancer patients. The gain- and loss-of-function of miR-146a-5p modulated the response to trastuzumab. Furthermore, the overexpression of miR-146a-5p increased migration and angiogenesis, and promoted cell cycle progression by reducing CDKN1A expression. Exosomes from trastuzumab-resistant cells showed a high level of miR-146a-5p expression compared with the parental cells. In addition, the co-culture with resistant cells' exosomes was able to decrease in sensitivity and increase the migration capacities in trastuzumab-sensitive cells, as well as angiogenesis in HUVEC-2 cells. Collectively, these data support the role of miR-146a-5p in resistance to trastuzumab, and demonstrate that it can be transferred by exosomes conferring resistance properties to other cells.
Insights
MicroRNA miR-146a-5p promotes trastuzumab resistance in HER2-positive breast cancer by affecting cell cycle and migration. It can be transferred via exosomes, spreading resistance to sensitive cells.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Trastuzumab therapy significantly benefits HER2-positive breast cancer patients.
- Therapeutic resistance remains a major clinical obstacle in HER2-positive breast cancer treatment.
Purpose of the Study:
- To investigate the role of microRNAs in trastuzumab resistance in HER2-positive breast cancer.
- To identify specific microRNAs involved in acquired resistance to trastuzumab.
Main Methods:
- MicroRNA array analysis of parental and trastuzumab-resistant HER2-positive breast cancer cell lines.
- Gain- and loss-of-function studies of miR-146a-5p.
- Analysis of exosome-mediated transfer of miR-146a-5p.
- Assessment of cell migration, angiogenesis, and cell cycle progression.
Main Results:
- miR-146a-5p was identified as a significantly dysregulated microRNA in trastuzumab-resistant cells.
- High miR-146a-5p expression correlated with shorter disease-free survival in patients.
- Modulating miR-146a-5p levels affected trastuzumab sensitivity.
- Overexpression of miR-146a-5p promoted cell migration, angiogenesis, and cell cycle progression by downregulating CDKN1A.
- Exosomes from resistant cells contained high levels of miR-146a-5p and transferred resistance properties to sensitive cells and promoted angiogenesis.
Conclusions:
- miR-146a-5p plays a crucial role in trastuzumab resistance in HER2-positive breast cancer.
- Exosomes mediate the intercellular transfer of miR-146a-5p, contributing to resistance.
- miR-146a-5p represents a potential therapeutic target for overcoming trastuzumab resistance.
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