Lead Bioaccumulation Drives Genomic Instability and Apoptotic Resistance in Human Breast Cancer

Introduction: Lead (Pb) is a widespread environmental toxicant classified by IARC as a probable human carcinogen, yet its mechanistic involvement in breast cancer remains poorly defined. Epidemiological studies suggest an association between Pb exposure and breast cancer risk, but tissue-level data linking Pb accumulation to molecular cancer features are limited. Understanding whether Pb bioaccumulates within breast tumors and influences key cancer hallmarks may reveal overlooked environmental determinants of breast cancer progression. Methods: Formalin-fixed paraffin-embedded breast cancer samples from 26 female patients. Lead concentration was quantified using inductively coupled plasma mass spectrometry (ICP-MS). Whole-genome sequencing and RNA-seq were performed on frozen tumor aliquots (n = 21), enabling assessment of Tumor Mutational Burden (TMB), Microsatellite Instability (MSI), mutational signatures, and PAM50 molecular subtypes. Spearman correlation, bootstrap confidence intervals, and non-parametric tests assessed relationships between Pb concentration and clinicopathological or molecular variables. Results: Lead was detected in 100% of breast cancer samples, with a mean concentration of 18.2 ± 16.2 mg/kg (range: 0.2-310 mg/kg). Lead levels showed no association with age or classical pathological features, including histologic grade (p = 0.8) and lymph-node metastasis (p = 0.6). Notably, Pb concentration was independent of PAM50 subtypes, suggesting that Pb accumulation reflects a biological dimension distinct from established intrinsic classifications.A significant relationship emerged between Pb accumulation and genomic instability. Lead concentration strongly correlated with TMB (ρ = 0.87; p < 0.0001) and MSI (ρ = 0.79; p < 0.0001). Tumors with the highest Pb levels also harbored TP53 missense mutations and frameshift deletions, underscoring a link between Pb burden and DNA repair pathway dysregulation. These findings support a model in which Pb bioaccumulation promotes mutational processes, potentially via disruption of mismatch repair mechanisms.Pb concentration was also positively associated with expression of BCL2 (ρ = 0.66; p = 0.001) and p53 (ρ = 0.65; p = 0.002), pointing toward enhanced resistance to regulated cell death. Conclusion: Data here reported highlighted the need to incorporate environmental metal burden into breast cancer risk assessment particularly for patients exhibiting elevated TMB/MSI who may benefit from immunotherapy.