Host-Derived Proteomic Profiling of Human and Canine Mammary Tumor Xenografts Identifies Enrichment of Lipid Metabolism-Related Pathways

Abstract

Abstract Breast cancer is the most frequently diagnosed cancer in women worldwide and one of the most common malignancies in dogs. Notable clinical, hormonal and molecular similarities between both species suggest that dogs may serve as a valuable comparative oncology model. Alterations in lipid homeostasis and metabolism are closely associated with the acquisition of cancer hallmarks. In this study, a comparative proteomic analysis of murine host-derived proteins was performed in cell line-derived xenograft (CDX) models generated from human triple-negative breast cancer cell line (MDA-MB-231) and a canine mammary carcinoma cell line (CMT-U27). Using LC-MS/MS and species-resolved proteomics, tumor-associated changes in the host proteome were characterized across models. In total, 577 proteins were differentially identified in tumor tissues compared with healthy mammary gland samples in this interspecies CDX comparison, with 51.99% showing increased and 46.79% decreased relative abundance, while a small proportion displayed opposite regulation patterns between models. Functional enrichment analysis revealed that several biological processes were altered, including pathways related to lipid metabolism. Moreover, proteins involved in lipid pathways showed a moderate level of concordance between models ( r > 0.6, Mann-Whitney U test p < 0.05). Overall, these findings provide a descriptive overview of host-derived proteomic alterations in interspecies mammary tumor CDX models and suggest that lipid metabolism-related pathways may be involved in tumor-associated microenvironmental changes. This study should be considered exploratory and hypothesis-generating, providing a basis for future studies incorporating orthogonal validation and controlled experimental designs.