FGFR4-associated APOBEC3 mutagenesis characterizes HER2-enriched subtype of human breast cancer

BACKGROUND: Characterising somatic mutation profiles in human breast cancer (HBC) is essential for understanding tumour progression and guiding therapeutic strategies. METHODS: We performed genomic and transcriptomic analyses to profile the mutational landscape of HBC. In addition to our primary analysis of HBC, we conducted comparative genomic analyses to evaluate the extent to which these mutational processes are recapitulated in canine mammary tumour (CMT), a widely proposed translational model. RESULTS: APOBEC3 (A3)-associated mutations were extensive in HBC but largely absent in CMT, likely due to structural differences in A3 proteins and lower basal expression. Transcriptomic stratification of HBC by A3 activity uncovered that tumours with A3 activity showed a strong association with the PAM50-HER2-Enriched (HER2E) subtype, and FGFR4 was significantly correlated with the expression and enzymatic function of APOBEC3A/B. CONCLUSIONS: These findings demonstrate that CMT is an unsuitable model for A3-mediated mutagenesis, emphasising the need to consider the limitations of cross-species mutational modelling in comparative oncology. Moreover, this study identifies a potential regulatory association between FGFR4 and A3, offering insights into the underlying mechanisms of A3-driven mutagenesis and suggesting that the FGFR4-A3 activity could be considered alongside other molecular biomarkers for the classification of the HER2E subtype.