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Breast Cancer-Derived Extracellular Vesicle miR-425-5p (miR-425) Promotes Brain Metastasis via Activating Astrocytes Through the Novel miR-425-ZNF24-CCL8 Signaling Axis.

Overview

Authors: Grace L Wong1,2, Munazza S Khan1,3, Sara Manore1,2, Shivani Bindal1, Ravi Singh2, Hui-Wen Lo1,2,3,4,5,6,7
  1. Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (G.L.W.); (M.S.K.); (S.M.); (S.B.)
  2. Graduate School of Biomedical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
  3. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  4. Department of Cell Biology and Genetics, College of Medicine, Texas A&M University Health Science Center at Houston, Bryan, TX 77807-3260, USA
  5. Department of Translational Medicine, Naresh K. Vashisht College of Medicine, Texas A&M Health Science Center, Texas A&M University, Bryan, TX 77807-3260, USA
  6. Institute of Biosciences & Technology, Texas A&M Health Science Center, Texas A&M University, Houston, TX 77030, USA
  7. Department of Cell Biology and Genetics, Naresh K. Vashisht College of Medicine, Texas A&M Health Science Center, Texas A&M University, 4209 MREB II, 8447 John Sharp Parkway, Bryan, TX 77807-3260, USA
Journal: International journal of molecular sciences, volume 27, issue 7, article 3197
Dates: received 4 February 2026; accepted 23 March 2026; published online 31 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.3390/ijms27073197 · PMID 41977380 · PMCID PMC13073527 · OpenAlex W7147574302
Open access: gold, a free copy (OpenAlex)
Categories: human (organism), mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: breast cancer brain metastasis, MicroRNAs, miR-425, ZNF24, CCL8
MeSH: Astrocytes*, Brain Neoplasms*, Breast Neoplasms*, Extracellular Vesicles*, Kruppel-Like Transcription Factors*, MicroRNAs*, Animals, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Signal Transduction (* major topic)
Topic: Extracellular vesicles in disease (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: NCI NIH HHS (R01 CA228137, P30 CA012197, R21 CA286225); Dod (W81XWH-19-1-0072, W81XWH-19-1-0753, HT9425-24-1-0889, W81XWH-20-1-0044); NIH HHS (R01CA228137, R21CA286225); METAvivor (Translational Research Award)
Citations: not cited yet (Europe PMC); 80 references in the paper

Abstract

Mechanisms underlying breast cancer brain metastasis (BCBM) are still not well understood. Here, we identified that BCBM patient serum contained extracellular vesicles (EVs) with high levels of microRNAs (miRNAs)-107 and -425. Levels of miR-107 and miR-425 were elevated in brain metastases, and the elevation was associated with poor patient prognoses. Ectopic expression of miR-107 and miR-425 promoted mammospheres; however, the inhibition of miR-425, but not miR-107, suppressed breast cancer mammosphere formation. We further observed that EVs from miR-425-overexpressing breast cancer cells strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-425-activated astrocytes promoted mammospheres. To elucidate how miR-425 activates astrocytes, we found that, within astrocytes, miR-425 suppressed the expression of transcription factor ZNF24, which downregulated CCL8 cytokine expression/secretion, leading to the subsequent activation of astrocytes. Using a mouse study, we further determined the role of miR-425 in brain metastasis formation and observed that miR-425-overexpressing breast cancer cells exhibited significantly more aggressive growth in mouse brains compared to control cells. Immunohistochemistry and immunofluorescence analyses of mouse brain metastases revealed that miR-425-overexpressing tumors exhibited significantly increased activation, intratumoral accumulation, and proliferation of astrocytes, and a decrease in ZNF24 expression compared to control tumors. Together, our findings demonstrate, for the first time, that breast cancer EV-derived miR-425 promotes BCBM via activating astrocytes in the brain microenvironment through the novel EV-miR-425-ZNF24-CCL8 signaling axis.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors on request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 5 keywords, 14 MeSH terms, 4 funders, 80 references.

Cite

This paper

Wong, G. L., Khan, M. S., Manore, S., Bindal, S., Singh, R., & Lo, H.-W. (2026). Breast Cancer-Derived Extracellular Vesicle miR-425-5p (miR-425) Promotes Brain Metastasis via Activating Astrocytes Through the Novel miR-425-ZNF24-CCL8 Signaling Axis. International journal of molecular sciences, 27(7), 3197. https://doi.org/10.3390/ijms27073197

BibTeX

@article{wong2026breast,
author = {Wong, Grace L and Khan, Munazza S and Manore, Sara and Bindal, Shivani and Singh, Ravi and Lo, Hui-Wen},
title = {{Breast Cancer-Derived Extracellular Vesicle miR-425-5p (miR-425) Promotes Brain Metastasis via Activating Astrocytes Through the Novel miR-425-ZNF24-CCL8 Signaling Axis}},
journal = {International journal of molecular sciences},
year = {2026},
month = mar,
volume = {27},
number = {7},
pages = {3197},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {1422-0067},
doi = {10.3390/ijms27073197},
url = {https://doi.org/10.3390/ijms27073197},
pmid = {41977380},
pmcid = {PMC13073527}
}

RIS

TY - JOUR
AU - Wong, Grace L
AU - Khan, Munazza S
AU - Manore, Sara
AU - Bindal, Shivani
AU - Singh, Ravi
AU - Lo, Hui-Wen
TI - Breast Cancer-Derived Extracellular Vesicle miR-425-5p (miR-425) Promotes Brain Metastasis via Activating Astrocytes Through the Novel miR-425-ZNF24-CCL8 Signaling Axis
T2 - International journal of molecular sciences
J2 - Int J Mol Sci
PY - 2026
DA - 2026/03/31
VL - 27
IS - 7
SP - 3197
SN - 1422-0067
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/ijms27073197
UR - https://doi.org/10.3390/ijms27073197
LA - en
ER -

CSL-JSON

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