# Alterations in Tumor Aggression Following Androgen Receptor Signaling Restoration in Canine Prostate Cancer Cell Lines

## TL;DR

Restoring androgen receptor signaling in canine prostate cancer cell lines leads to varied effects on tumor aggression, highlighting differences between cell lines.

## Contribution

The study demonstrates cell line-specific effects of androgen receptor restoration on tumor aggression in dogs, a natural model for prostate cancer.

## Key findings

- AR restoration in 1508 cells reduced clonogenicity, viability, migration, invasion, and increased tumor suppressor NKX3.1.
- In 1258 cells, AR increased migration and invasion, with EMT markers upregulated and vimentin knockdown reversing migration effects.
- AR effects varied across cell lines, with suppression in 1508, partial effects in Leo, and EMT-driven aggression in 1258.

## Abstract

In prostate cancer (PCa), androgens upregulate tumorigenesis, whereas in benign tissue, the revival of androgen receptor (AR) signaling suppresses aggressive behaviors, suggesting therapeutic potential. Dogs, natural PCa models, often lack AR in PCa. We restored AR in dog PCa to investigate resultant characteristics. Three AR-null canine PCa lines (1508, Leo, 1258) were transfected with canine wild-type AR and treated with dihydrotestosterone (DHT). In 1508, AR restoration decreased clonogenicity (p = 0.03), viability (p = 0.004), migration (p = 0.03), invasion (p = 0.01), and increased expression of the tumor suppressor NKX3.1, an AR transcriptional target (p = 0.001). In Leo, AR decreased clonogenicity (p = 0.04) and the expression of another AR transcriptional target FOLH1 (p < 0.001) and increased the expression of NKX3.1 (p = 0.01). In 1258, AR increased migration (p = 0.006) and invasion (p = 0.03). Epithelial–mesenchymal transition (EMT) marker (Vimentin, N-cadherin, SNAIL1) expression increased with AR restoration in Leo and 1258 but not 1508; siRNA vimentin knockdown abrogated AR-induced 1258 migration only. Overall, 1508 showed AR-mediated tumor suppression; AR affected proliferation in Leo but not migration or invasion; and EMT and AR regulated migration and invasion in 1258 but not proliferation. This study highlights the heterogeneous nature of PCa in dogs and cell line-specific effects of AR abrogation on aggressive behaviors.