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

Area of Science:

• Oncology
• Molecular Biology
• Comparative Pathology

Background:

• Androgen receptor (AR) signaling plays a dual role in prostate cancer (PCa), promoting tumorigenesis in cancerous tissue but suppressing aggressive behaviors in benign tissue.
• Canine PCa is a natural model for human PCa, yet canine PCa often lacks AR expression, limiting its utility in studying AR's therapeutic potential.
• Understanding AR's function in PCa is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the effects of restoring AR signaling in AR-null canine PCa cell lines.
• To characterize the resultant changes in tumorigenic behaviors, including clonogenicity, viability, migration, and invasion.
• To explore the role of AR in regulating tumor suppressor genes and epithelial-mesenchymal transition (EMT) markers.

Main Methods:

• Three AR-null canine PCa cell lines (1508, Leo, 1258) were transfected with canine wild-type AR.
• Cells were treated with dihydrotestosterone (DHT) to activate the restored AR.
• Assays were performed to measure clonogenicity, viability, migration, and invasion. Gene expression of NKX3.1, FOLH1, Vimentin, N-cadherin, and SNAIL1 was analyzed. siRNA-mediated knockdown of Vimentin was used to assess its role in AR-induced migration.

Main Results:

• In the 1508 cell line, AR restoration significantly decreased clonogenicity, viability, migration, and invasion, while increasing the tumor suppressor NKX3.1 expression.
• In the Leo cell line, AR decreased clonogenicity and altered FOLH1 and NKX3.1 expression. EMT markers increased, but AR did not affect migration or invasion.
• In the 1258 cell line, AR increased migration and invasion, accompanied by increased EMT marker expression. AR did not affect proliferation in this line.

Conclusions:

• AR restoration has heterogeneous effects on canine PCa cell lines, demonstrating cell line-specific responses.
• The 1508 cell line exhibited AR-mediated tumor suppression, while Leo showed effects on proliferation and 1258 showed AR- and EMT-driven migration and invasion.
• These findings underscore the complexity of AR signaling in PCa and highlight the importance of considering cell line-specific characteristics in canine models.