Conserved mRNA expression patterns of the Klotho family in canine mammary tumors and human breast cancer

Canine mammary tumors (CMTs) are a naturally occurring comparative model for human breast cancer (HBC) due to their genetic, molecular, and epidemiological similarities. Our previous study in HBC suggested that αKlotho and βKlotho function as tumor suppressors, but γKlotho has an oncogenic effect. Strikingly, we found γKlotho to be overexpressed in more than 65% of triple-negative breast cancer (TNBC) cases. However, the expression and role of Klothos in CMTs have not been investigated. In this study, we analyzed the mRNA expression of the Klotho family, hormone receptors, and FGFRs in 67 fresh-frozen and archived formalin-fixed paraffin-embedded (FFPE) CMTs stratified by histologic subtype. We validated our findings with a publicly available dataset comprising 157 CMTs. Compared with adjacent normal tissue, we found that αKlotho and βKlotho mRNA levels were reduced in CMTs, but γKlotho mRNA expression was increased, with higher levels observed in more aggressive tumors. Differential expression analysis comparing γKlotho-high and -low tumors identified 52 genes that were similarly dysregulated in human and canine datasets, with enrichment in androgen receptor (AR), VEGF, and ERK signaling pathways. The similar expression patterns of Klothos in HBC and CMTs suggest Klothos may have conserved roles in CMT pathogenesis. Further investigation is warranted to determine γKlotho's potential as a prognostic biomarker or therapeutic target in humans and dogs.