Author ORCID Identifier
0000-0001-7447-8769
Date of Graduation
5-2025
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Hui-Wen Lo
Committee Member
Yoshua Esquenazi Levy
Committee Member
Tae Jin Lee
Committee Member
Kai Sun
Committee Member
Aria Vaishnavi
Abstract
In this study, we aimed to identify microRNAs (miRNAs) that may play important roles in breast cancer brain metastasis (BCBM). To this end, we conducted miRNA-sequencing of extracellular vesicles isolated from the serum samples of 6 BCBM patients and 8 Stage I/II/III breast cancer patients, and identified 49 circulating miRNAs that were upregulated in BCBM patients compared to Stage I/II/III breast cancer. Upon further analysis, we identified miR-4732-3p to be upregulated in brain-tropic triple-negative breast cancer (TNBC) cell lines, compared to parental lines. MiR-4732-3p overexpression increased metastatic properties of TNBC cells, including proliferation, migration, invasion, and maintenance of a mesenchymal state. Additionally, we observed that extracellular vesicles secreted from miR-4732-3p-overexpressing TNBC cells significantly activated astrocytes. To determine how miR-4732-3p-activated astrocytes may activate further astrocytes and also BCBM cells, we conducted cytokine arrays to identify significantly dysregulated cytokines, and found that multiple cytokines including FLT3LG can be upregulated in miR-4732-3p-overexpressing astrocytes. We further showed that FLT3LG significantly activates astrocytes and promotes astrocyte proliferation. In agreement with the cytokine array results, FLT3LG mRNA is upregulated in astrocytes overexpressing miR-4732-3p. Finally, using TargetScan and GeneCards, we identified multiple potential miR-4732-3p target genes that are transcriptional repressors of FLT3LG, suggesting their potential roles in activating FLT3LG expression. These results collectively demonstrate that breast cancer-derived miR-4732-3p may play a novel important role in BCBM by promoting metastatic properties of BCBM cells, and activating astrocytes in the brain-metastatic tumor microenvironment through FLT3LG secretion.
Keywords
Breast Cancer, Triple-Negative Breast Cancer, MicroRNA, Breast Cancer Brain Metastasis, Brain Microenvironment, Astrocyte Activation, Cytokines