EGFR Signaling in Canine Mammary Tumors: Molecular Mechanisms, Clinicopathological Correlations, Comparative Aspects with Human Breast Cancer, and Translational Opportunities

Canine mammary tumors (CMTs) are the most common neoplasms in intact female dogs and represent a spontaneous, immune competent model for human breast cancer (HBC), particularly triple negative/basal like subtypes. Epidermal growth factor receptor (EGFR/ErbB1/HER1) is overexpressed in approximately 42–55% of malignant CMTs and activates conserved downstream pathways, including RAS/RAF/MEK/ERK (MAPK), PI3K/AKT/mTOR (aberrations in up to 61.7% of cases with recurrent PIK3CA H1047R hotspot mutations), PLCγ/PKC, JAK/STAT3, and nuclear EGFR signalling. This review synthesises EGFR expression patterns, detailed signalling mechanisms with crosstalk (angiogenesis, PD-L1, COX-2), clinicopathological and prognostic associations, therapeutic targeting, translational value, with HBC genomic conservation being full, although CMTs exhibits lower ERBB2 expansion. Preclinical data have assisted caninized anti-EGFR antibodies, PI3Kα inhibitors (alpelisib), tyrosine kinase inhibitors, and natural compounds. CMTs offer unique opportunities for precision oncology when contextualized within different canine cancer models. Key deficits and future directions are highlighted for both veterinary and human benefit.