Abstract
TP53 mutations frequently co-occur with HER2 amplification in breast cancer, yet how mutant p53 influences HER2-positive (HER2+) tumor biology remains incompletely understood, as does whether distinct hotspot mutations exert allele-specific effects. Here, we investigated the effects of p53R172H and p53R245W in genetically engineered HER2+ mammary tumor models. Tumor latency, incidence, growth, and histopathology were comparable between HER2-only tumors and those with mutant p53; unexpectedly, lung metastases occurred less frequently in tumors with mutant p53. HER2+ tumors with p53R172H exhibited greater Trp53 loss of heterozygosity than those with p53R245W. Transcriptomic analyses revealed mutant p53-associated activation of cell-cycle, DNA-replication and -repair, chromatin, RNA-processing, and immune pathways, whereas HER2-only tumors showed enrichment of metabolic and nuclear receptor programs. The two alleles shared proliferative programs but displayed distinct metabolic, stress-response, cell-communication, cytoskeletal, and microenvironmental signatures. Metastatic status revealed state-dependent reprogramming: non-metastatic HER2+ tumors with mutant p53 showed suppression of metastasis-associated pathways, whereas their metastatic counterparts activated these programs. Allele-specific differences were more pronounced in non-metastatic tumors. Whole-exome sequencing identified candidate alterations in tumor-suppressive and oncogenic regulators. Collectively, these findings demonstrate allele- and metastatic-state-dependent molecular reprogramming by p53R172H and p53R245W in HER2+ breast cancer, highlighting a complex relationship between mutant p53 and metastatic progression.