Comprehensive Genomic Profiling of Androgen-Receptor-Negative Canine Prostate Cancer

Abstract

Canine carcinomas have been considered natural models for human diseases; however, the genomic profile of canine prostate cancers (PCs) has not been explored. In this study, 14 PC androgen-receptor-negative cases, 4 proliferative inflammatory atrophies (PIA), and 5 normal prostate tissues were investigated by array-based comparative genomic hybridization (aCGH). Copy number alterations (CNAs) were assessed using the Canine Genome CGH Microarray 4 × 44K (Agilent Technologies). Genes covered by recurrent CNAs were submitted to enrichment and cross-validation analysis. In addition, the expression levels of TP53, MDM2 and ZBTB4 were evaluated in an independent set of cases by qPCR. PC cases presented genomic complexity, while PIA samples had a small number of CNAs. Recurrent losses covering well-known tumor suppressor genes, such as ATM, BRCA1, CDH1, MEN1 and TP53, were found in PC. The in silico functional analysis showed several cancer-related genes associated with canonical pathways and interaction networks previously described in human PC. The MDM2, TP53, and ZBTB4 copy number alterations were translated into altered expression levels. A cross-validation analysis using The Cancer Genome Atlas (TCGA) database for human PC uncovered similarities between canine and human PCs. Androgen-receptor-negative canine PC is a complex disease characterized by high genomic instability, showing a set of genes with similar alterations to human cancer.

A Comparative in Silico Analysis of CD24’s Prognostic Value in Human and Canine Prostate Cancer

“…Among models of prostate cancer, mice and dogs have been widely used [ 4 , 31 , 32 , 33 ]. Usui et al [ 31 ] established an organoid model of canine prostate cancer for new therapeutic approaches.…”

“…However, no further studies evaluated the reliability of this model in predicting the anti-tumor response of different drugs. Although mice models have been used for human prostate cancer [ 34 ], dogs develop prostate cancer naturally, thus resembling human disease [ 32 ]. Several studies have evaluated the efficacy of different anti-cancer drugs in canine models of human cancers [ 35 , 36 , 37 ], particularly immune therapy strategies for canine osteosarcomas [ 35 ], use of monoclonal antibodies in canine oral melanomas [ 36 ] and use of sorafenib in hepatocellular carcinomas [ 37 ].…”

E-Cadherin Downregulation is Mediated by Promoter Methylation in Canine Prostate Cancer

“…Dogs have been reported as a model for human PC and the knowledge regarding molecular aspects of canine PC has increased in recent years (Fonseca-Alves et al, 2018a; Costa et al, 2019; Laufer-Amorim et al, 2019; Rivera-Calderón et al, 2019). These recent studies bring new evidence that canine PC can represent a model to human castration-resistant prostate cancer (CRPC) (Laufer-Amorim et al, 2019).…”

“…Dogs have been reported as a model for human PC and the knowledge regarding molecular aspects of canine PC has increased in recent years (Fonseca-Alves et al, 2018a; Costa et al, 2019; Laufer-Amorim et al, 2019; Rivera-Calderón et al, 2019). These recent studies bring new evidence that canine PC can represent a model to human castration-resistant prostate cancer (CRPC) (Laufer-Amorim et al, 2019). Usually, canine PC lacks NKX3.1, PTEN (Fonseca-Alves et al, 2013; Fonseca-Alves et al, 2018a; Fonseca-Alves et al, 2018b), and androgen receptor expression (Laufer-Amorim et al, 2019) resembling human CRPC.…”

“…These recent studies bring new evidence that canine PC can represent a model to human castration-resistant prostate cancer (CRPC) (Laufer-Amorim et al, 2019). Usually, canine PC lacks NKX3.1, PTEN (Fonseca-Alves et al, 2013; Fonseca-Alves et al, 2018a; Fonseca-Alves et al, 2018b), and androgen receptor expression (Laufer-Amorim et al, 2019) resembling human CRPC. Besides that, canine PC shows alterations in TP53, C-MYC, and MDM2 protein expression (Fonseca-Alves et al, 2013; Fonseca-Alves et al, 2018b).…”