Functional Distinction between the Full-Length Human Androgen Receptor and Its Splicing Variants in Castration-Resistant Prostate Cancer
Rong Hu, Changxue Lu, Angelo M De Marzo, William B Isaacs, Jun Luo. University of Wisconsin, Madison, WI; The Johns Hopkins University, Baltimore, MD
Background: Multiple androgen receptor splicing variants (AR-Vs) arising in castration-resistant prostate cancer (CRPC) have recently been decoded and characterized. AR-Vs lack the AR ligand-binding domain, the intended target of all endocrine therapies for prostate cancer, suggesting a key mechanism underlying development of CRPC. However, the abundance of individual AR-V levels relative to the canonical full-length AR (AR-FL) is low, and both AR-FL and AR-Vs are overexpressed in CRPC. Due to sustained supply of tissue androgens under castrate conditions, AR signaling in CRPC may continue to rely on the canonical AR-FL. The goal of this study is to determine the relative importance of AR-FL and AR-Vs in CRPC.
Design: A set of detection and targeting tools were first developed to differentiate the AR-FL and AR-Vs. Genome-wide expression changes mediated by AR-FL and AR-Vs were investigated in various treatment settings using cell line models of CRPC that recapitulate the relative expression levels of AR-FL and AR-Vs. A variant-specific antibody was developed and used to detect AR-V7 expression in CRPC specimens from patients who developed obstructive urinary symptoms following hormone therapies.
Results: An acute adaptive shift toward AR-V-mediated signaling was observed after suppression of AR-FL signaling. AR-V7, one of the most abundant AR-Vs with a validated protein product, is dramatically induced (up to 100 fold) following treatment mimicking endocrine therapies. Both the endogenously induced AR-V7 and exogenously transfected AR-V7 activate an expression signature enriched for cell cycle genes, whereas activation of AR-FL is associated with a signature enriched for genes related to cellular synthesis, metabolism, and differentiation. In clinical CRPC specimens, AR-V7, but not the AR-FL, is positively correlated with UBE2C, a validated cell cycle gene involved in castration-resistant prostate cancer cell growth.
Conclusions: The cumulative in vitro and in vivo evidence supports a functional dichotomy between AR-FL and AR-Vs in CRPC. The emergence of AR-V mediated signaling may be an indicator of castration-resistant prostate cancer progression. Future therapies for CRPC patients should be designed to overcome this adaptive mechanism of drug resistance that may be manifested in at least a subset of CRPC patients.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 140, Monday Morning