TY  - EJOU
AU  - Borzone, Francisco Raúl 
AU  - Giorello, María Belén 
AU  - Freire, Agustina 
AU  - Martinez, Leandro Marcelo 
AU  - Feldman, Leonardo 
AU  - Dimase, Federico 
AU  - Evelson, Pablo 
AU  - Larripa, Irene 
AU  - Batagelj, Emilio 
AU  - Cid, Marcela Beatriz González 
AU  - Chasseing, Norma Alejandra 

TI  - Oxidative Stress Footprints in Bone Marrow Mesenchymal Stem Cells from Untreated Advanced Breast Cancer
T2  - Oncology Research

PY  - 2026
VL  - 34
IS  - 4
SN  - 1555-3906

AB  -  <b>Backgrounds:</b> Breast cancer metastasis remains the leading cause of mortality and frequently targets the bone. Breast cancer cells release soluble factors and extracellular vesicles that disrupt bone marrow (BM)/bone homeostasis, promoting osteoclastogenesis and the accumulation of senescent cells. In line with updated cancer hallmarks, senescent mesenchymal stem/ stromal cells (MSCs), osteoblasts, and osteocytes contribute to remodeling of the BM microenvironment, thereby favoring pre-metastatic niche (PMN) formation and subsequent bone metastasis. We previously demonstrated that untreated stage III-B breast cancer patients (BCPs) exhibit increased oxidative stress and elevated reactive oxygen species (ROS) levels, accompanied by senescent and functionally impaired BM-MSCs—key regulators of BM/bone homeostasis. In the present study, we sought to identify the molecular targets affected by oxidative stress that drive MSC senescence in these patients. <b>Methods:</b> BM-MSCs were isolated from untreated stage III-B BCPs and healthy volunteers (HVs). Oxidative stress responses were evaluated by quantitative real-time PCR (qRT-PCR) analysis of stress- and antioxidant-related genes. Oxidative damage to DNA, proteins, and lipids was assessed using alkaline comet assay, chromosomal aberration (CAs) analysis, micronuclei (MN) and nuclear blebs (NBs) quantification, protein carbonyl content, and detection of 4-hydroxynonenal (4-HNE) adducts. The MSC secretome was analyzed by label-free quantitative proteomics followed by Gene Ontology enrichment analysis. <b>Results:</b> Our results show that elevated oxidative stress in BCPs induces the overexpression of oxidative stress–related and antioxidant response genes in BM-MSCs; however, this response is insufficient to prevent extensive ROS-induced damage to deoxyribonucleic acid (DNA), proteins, and lipids. In addition, proteomic analysis of the BM-MSC secretome revealed a distinct protein expression profile in BCPs compared with HVs. <b>Conclusions:</b> Together, these findings highlight oxidative stress–induced MSC damage as a key mechanism contributing to PMN formation and suggest potential therapeutic targets to mitigate bone metastasis in advanced breast cancer.
KW  - Mesenchymal stem/stromal cells; bone marrow; breast cancer; reactive oxygen species damage; secretome; pre-metastatic niche; bone metastasis

DO  - 10.32604/or.2026.074321