Aging-associated differences in mammary tumor-initiating populations and immune evasion pathways in breast cancer.

Aging is a major risk factor for breast cancer, yet how it shapes tumor development, molecular phenotype, and immune evasion remains incompletely understood. Deciphering how aging influences cancer evolution is critical for improving risk assessment, prevention, and treatment. Here, using a N-nitroso-N-methylurea (NMU)-induced rat mammary tumor model that recapitulates key features of human breast cancer, we integrated bulk and single-cell transcriptomics, whole-exome sequencing, and histopathological analysis to dissect age-associated differences in mammary tumorigenesis. We found that the age at NMU exposure critically influences tumor incidence, mutational burden, molecular subtype, and the tumor immune microenvironment. Tumors arising in aged rats originated from aging luminal progenitor-like cells, exhibited increased genomic instability, reduced immune cell infiltration, and impaired antigen presentation linked to loss of heterozygosity at chromosome (Chr) 20p. The age-associated epithelial and immune changes we identified were conserved in human breast cancers, where the loss of the homologous Chr 6p region correlated with reduced lymphocyte infiltration and shorter relapse-free survival. These findings reveal that aging profoundly affects tumor-initiating cell populations and promotes immune evasion through chromosomal instability-driven defects in antigen presentation. Our work provides a molecular basis for understanding disease onset and progression that may impact efficacy of immunotherapy in older breast cancer patients.