AbstractBackgroundRegulator of G‐protein signaling 2 (RGS2) is a multifaceted protein with a prognostic value in hormone‐naïve prostate cancer (PC). It has previously been associated with the development of castration resistance. However, RGS2 expression in clinical specimens of castration‐resistant prostate cancer (CRPC) and its clinical relevance has not been explored. In the present study, RGS2 was assessed in CRPC and in relation to the development of castration resistance.MethodsIn the present study, RGS2 expression was evaluated with immunohistochemistry in patient materials of hormone‐naïve and castration‐resistant primary tumors, also in matched specimens before and after 3 months of androgen deprivation therapy (ADT). Cox regression and Kaplan‐Meier curves were used to evaluate the clinical significance of RGS2 expression. RGS2 expression in association to castration‐resistant growth was assessed experimentally in an orthotopic xenograft mouse model of CRPC. In vitro, hormone depletion of LNCaP and enzalutamide treatment of LNCaP, 22Rv1, and VCaP was performed to evaluate the association between RGS2 and the androgen receptor (AR). Stable RGS2 knockdown was used to evaluate the impact of RGS2 in association to PC cell growth under hormone‐reduced conditions. Gene and protein expression were evaluated with quantitative polymerase chain reaction and Western blot analysis, respectively.ResultsRGS2 expression is increased in CRPC and enriched under ADT. Furthermore, a high RGS2 level is prognostic for poor cancer‐specific survival for CRPC patients and significantly reduced failure‐free survival (FFS) after an initiated ADT. Additionally, the prognostic value of RGS2 outperforms prostate‐specific antigen (PSA) in terms of FFS. The present study furthermore suggests that RGS2 expression is reflective of AR activity. Moreover, low RGS2‐expressing cells display hampered growth under hormone‐reduced conditions, in line with the poor prognosis associated with high RGS2 expression.ConclusionsHigh levels of RGS2 are associated with aggressive forms of castration‐resistant PC. The results demonstrate that a high level of RGS2 is associated with poor prognosis in association with castration‐resistant PC growth. RGS2 alone, or in association with PSA, has the potential to identify patients that require additional treatment at an early stage during ADT.