Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases is Associated with Castration-Resistance and Short Survival

被引:400
作者
Hornberg, Emma [1 ]
Ylitalo, Erik Bovinder [1 ]
Crnalic, Sead [2 ]
Antti, Henrik [3 ]
Stattin, Par [2 ]
Widmark, Anders [4 ]
Bergh, Anders [1 ]
Wikstrom, Pernilla [1 ]
机构
[1] Umea Univ, Dept Med Biosci, Umea, Sweden
[2] Umea Univ, Dept Surg & Perioperat Sci Orthoped & Urol & Andr, Umea, Sweden
[3] Umea Univ, Dept Chem, Umea, Sweden
[4] Umea Univ, Dept Radiat Sci, Umea, Sweden
基金
瑞典研究理事会;
关键词
INHIBITOR ABIRATERONE ACETATE; APOPTOTIC CELL-DEATH; THERAPY RESISTANCE; ANTITUMOR-ACTIVITY; GROWTH; MUTATION; ANTIANDROGEN; PROGRESSION; ACTIVATION; MECHANISM;
D O I
10.1371/journal.pone.0019059
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival. Methodology/Principal Findings: Hormone-naive (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival. Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.
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页数:9
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