UC Davis

Prostate cancer (PCa) is the most common cancer in men. While initial treatments involve androgen deprivation therapies and targeting the androgen receptor (AR), a subset of patients eventually develop aggressive forms of PCa resistant to these treatments, leaving them with limited therapeutic options. Because of this, there is a critical need to identify an animal model that recapitulates the advanced stages of human PCa to facilitate the development of novel, effective therapeutics. Dogs present a unique opportunity as they naturally develop aggressive AR null PCa, resembling advanced human PCa. However, to effectively leverage dogs as models, it is essential to discern which animals are suitable for preclinical trials ante-mortem and understand the pathophysiology of androgen receptor signaling in dog PCa. In this study, we examined the clinicopathologic features of PCa in dogs to identify characteristics indicative of prostatic adenocarcinoma (PRAD), the most prevalent subtype in humans, compared to other types such as prostatic transitional cell carcinoma (P-TCC) in order to identify animals appropriate for preclinical trials. Our findings revealed associations between specific clinicopathologic features and different PCa subtypes in dogs, including strong association of hypoalbuminemia with PRAD and the presence of Melamed-Wolinska bodies and necrosis on cytology specimens with P-TCC. Additionally, we explored the red blood cell distribution width to albumin (RAR) ratio as a potential diagnostic marker to differentiate between PRAD and P-TCC, demonstrating its utility when a certain cut-off ratio was applied. Furthermore, we conducted a proof-of-concept study to investigate the outcomes of reconstituting AR signaling in AR null PRAD dog cell lines. We aimed to determine whether restoring AR signaling in these dog cell lines attenuates aggressive behaviors, as observed in human PCa cell lines. Our results showed varied responses across different cell lines, with AR signaling leading to the abrogation of aggressive behaviors in some cell lines resembling androgen-dependent PCa, while inciting more aggressive behavior in others resembling castration-resistant prostate cancer (CRPC). Overall, this foundational research lays the groundwork for utilizing dogs as valuable models for studying human PCa progression and provides insights into selecting appropriate dog PCa cell lines for in vitro studies and identifying suitable dog PCa patients for preclinical trials for emerging therapeutics.