TY - JOUR
T1 - Regulation of androgen receptor variants in prostate cancer
AU - Zhu, Yezi
AU - Luo, Jun
N1 - Funding Information:
Some of the work associated with the review paper was supported by National Institutes of Health Grants ( R01 CA185297 and P30 CA006973 ), Department of Defense Prostate Cancer Research Program Grants ( W81XWH-15-2-0050 ), Johns Hopkins Prostate SPORE Grant ( P50 CA058236 ), and the Prostate Cancer Foundation .
Publisher Copyright:
© 2020 Editorial Office of Asian Journal of Urology
PY - 2020/7
Y1 - 2020/7
N2 - Aberrant activation of androgen receptor (AR) signaling occurs in patients treated with AR-targeted therapies, contributing to the development of castration-resistant prostate cancer (CRPC) and therapeutic resistance. Over the past decade, many AR variants (AR-Vs) have been identified in prostate cancer cell lines and clinical CRPC specimens. These AR-Vs lack the COOH-terminal ligand-binding domain (LBD), and may mediate constitutively active AR signaling acquired following AR-targeting therapies. AR splice variant-7 (AR-V7), one of the most well characterized AR-Vs, can be reliably measured in tissue and liquid biopsy specimens, and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies (NHT) such as abiraterone and enzalutamide in men with metastatic CRPC (mCRPC). Given the important clinical implication of AR-Vs, this short review will focus on studies addressing how AR-Vs are regulated in prostate cancer. With regard to the molecular origin of AR-Vs, it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR signaling. Therapeutic targeting of the AR axis may result in active transcription of the AR gene, elevated activities of certain components of the mRNA splicing machinery, as well as AR genomic alterations, all of which may explain the molecular origin of AR-Vs. Although a unified hypothesis is currently lacking, existing data suggest that elevated expression of AR-Vs, which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed, is driven by both genomic and epigenomic features acquired in the development of CRPC.
AB - Aberrant activation of androgen receptor (AR) signaling occurs in patients treated with AR-targeted therapies, contributing to the development of castration-resistant prostate cancer (CRPC) and therapeutic resistance. Over the past decade, many AR variants (AR-Vs) have been identified in prostate cancer cell lines and clinical CRPC specimens. These AR-Vs lack the COOH-terminal ligand-binding domain (LBD), and may mediate constitutively active AR signaling acquired following AR-targeting therapies. AR splice variant-7 (AR-V7), one of the most well characterized AR-Vs, can be reliably measured in tissue and liquid biopsy specimens, and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies (NHT) such as abiraterone and enzalutamide in men with metastatic CRPC (mCRPC). Given the important clinical implication of AR-Vs, this short review will focus on studies addressing how AR-Vs are regulated in prostate cancer. With regard to the molecular origin of AR-Vs, it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR signaling. Therapeutic targeting of the AR axis may result in active transcription of the AR gene, elevated activities of certain components of the mRNA splicing machinery, as well as AR genomic alterations, all of which may explain the molecular origin of AR-Vs. Although a unified hypothesis is currently lacking, existing data suggest that elevated expression of AR-Vs, which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed, is driven by both genomic and epigenomic features acquired in the development of CRPC.
KW - Androgen receptor
KW - Androgen receptor splice variant-7
KW - Castration-resistant prostate cancer
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U2 - 10.1016/j.ajur.2020.01.001
DO - 10.1016/j.ajur.2020.01.001
M3 - Review article
C2 - 33024700
AN - SCOPUS:85081201790
SN - 2214-3882
VL - 7
SP - 251
EP - 257
JO - Asian Journal of Urology
JF - Asian Journal of Urology
IS - 3
ER -