Molecular Adaptations to Repeated Radiation Exposure in Triple-Negative Breast Cancer: Dysregulation of Cell Adhesion, Mitochondrial Function, and Epithelial–Mesenchymal Transition

TL;DR

This study explores how triple-negative breast cancer cells adapt to repeated radiation, leading to resistance and changes in cell adhesion and function.

Contribution

The study identifies specific molecular adaptations in radiation-resistant triple-negative breast cancer cells, including dysregulated cell adhesion and mitochondrial pathways.

Findings

Radiation-adapted cells showed reduced adhesion receptor expression and impaired cell adhesion to extracellular matrix substrates.

Mitochondrial dysfunction was observed with downregulation of oxidative phosphorylation genes and reduced membrane potential.

Epithelial–mesenchymal transition markers indicated increased migratory potential in radiation-adapted cells.

Abstract

Radiation resistance presents a significant challenge in the treatment of triple-negative breast cancer (TNBC). To investigate the molecular adaptations associated with radiation therapy resistance, MDA-MB-231 cells were subjected to a repeated radiation (RR) regimen totaling 57 Gy over 11 weeks, followed by clonal selection. The resulting radiation-adapted cells (MDA-MB-231RR) were analyzed using whole-transcriptome RNA sequencing, revealing substantial dysregulation of pathways related to cell adhesion, mitochondrial function, and epithelial–mesenchymal transition (EMT). These transcriptional changes were corroborated by functional assays. MDA-MB-231RR cells exhibited reduced expression of adhesion receptors (ITGB1, ITGA2, ITGA6) and extracellular matrix proteins (fibronectin, collagen, laminins), accompanied by significantly impaired cell adhesion to fibronectin, collagen, and laminin substrates. Mitochondrial dysfunction was supported by downregulation of oxidative phosphorylation genes (MTCO1, MTND1) and confirmed by JC-1 dye assays demonstrating a marked reduction in mitochondrial membrane potential. EMT-associated changes included increased mesenchymal markers and loss of epithelial markers (CTNNB1, SNAI2, CK19), consistent with enhanced migratory potential. Taken together, this study delineates key molecular features of radiation adaptation in TNBC, providing a foundation for the development of targeted therapies to overcome treatment resistance.

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