Investigating Klothos and microRNAs as potential novel prognostic markers and therapeutic targets for Human Breast Cancer (HBC) and Canine Mammary Carcinoma (CMC)

Breast cancer remains a leading cause of cancer-related mortality worldwide, with canine mammary carcinoma (CMC) emerging as a powerful comparative model to study cancer biology and therapy within the One Health framework. This dissertation aimed to identify novel molecular markers with diagnostic, prognostic, and therapeutic potential across species by integrating histopathological, transcriptomic, and small RNA sequencing approaches. The initial focus of my research centered on the Klotho protein family, regulators of aging and cellular homeostasis, which have been previously shown to act as tumor suppressors () and oncogenes showed unique expression signatures in both human breast cancer (HBC) and CMC. Building on this, comprehensive transcriptome profiling of CMC tissues, normal mammary tissues, and canine mammary carcinoma cell lines revealed unique gene expression signatures and enriched oncogenic pathways, uncovering networks related to chemoresistance, cell adhesion, and tumor progression. Further, microRNA sequencing identified conserved oncogenic and tumor-suppressive signatures, including differentially expressed miRNAs such as miR-206, miR-224, and miR-31, which regulate pathways critical for carcinogenesis. These findings highlight conserved molecular mechanisms between canine and human mammary tumors, expanding the pool of potential biomarkers with diagnostic and therapeutic relevance. By reinforcing the translational value of CMC in breast cancer research, this work advances comparative oncology and, through a One Health perspective, bridges veterinary and human medicine while laying the foundation for precision oncology strategies benefiting both species.