A role for androgen receptor variant 7 in sensitivity to therapy: Involvement of IGFBP-2 and FOXA1

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Localised PCa can be treated effectively, but most patients relapse/progress to more aggressive disease. One possible mechanism underlying this progression is alternative splicing of the androgen receptor, with AR variant 7(ARV7) considered to play a major role. Using viability assays, we confirmed that ARV7-positive PCa cells were less sensitive to treatment with cabazitaxel and an anti-androgen-enzalutamide. Also, using live-holographic imaging, we showed that PCa cells with ARV7 exhibited an increased rate of cell division, proliferation, and motility, which could potentially contribute to a more aggressive phenotype. Furthermore, protein analysis demonstrated that ARV7 knock-down was associated with a decrease in insulin-like growth factor-2 (IGFBP-2) and forkhead box protein A1(FOXA1). This correlation was confirmed in-vivo using PCa tissue samples. Spearman rank correlation analysis showed significant positive associations between ARV7 and IGFBP-2 or FOXA1 in tissue from patients with PCa. This association was not present with the AR. These data suggest an interplay of FOXA1 and IGFBP-2 with ARV7mediated acquisition of an aggressive prostate cancer phenotype.

Automated summary

Prostate cancer is a leading cause of cancer-related deaths in men, and the progression of the disease may be influenced by alternative splicing of the androgen receptor, particularly the AR variant 7(ARV7). ARV7-positive prostate cancer cells were found to be less sensitive to treatment and exhibited increased cell division, proliferation, and motility compared to ARV7-negative cells. Additionally, protein analysis showed a correlation between ARV7 and insulin-like growth factor-2 (IGFBP-2) and forkhead box protein A1(FOXA1), suggesting an interplay between these factors in the acquisition of an aggressive prostate cancer phenotype.