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Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
- Source :
-
PloS one [PLoS One] 2011 Apr 28; Vol. 6 (4), pp. e19059. Date of Electronic Publication: 2011 Apr 28. - Publication Year :
- 2011
-
Abstract
- 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.<br />Methodology/principal Findings: Hormone-naïve (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.<br />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.
- Subjects :
- Aged
Aged, 80 and over
Bone Neoplasms diagnosis
Bone Neoplasms pathology
Cell Cycle genetics
Cell Nucleus metabolism
Gene Expression Profiling
Humans
Ligands
Male
Middle Aged
Prognosis
Prostate cytology
Prostate metabolism
Prostate pathology
Protein Isoforms chemistry
Protein Isoforms genetics
Protein Isoforms metabolism
Protein Structure, Tertiary
RNA, Messenger genetics
RNA, Messenger metabolism
Receptors, Androgen chemistry
Receptors, Androgen metabolism
Survival Analysis
Bone Neoplasms genetics
Bone Neoplasms secondary
Gene Expression Regulation, Neoplastic
Orchiectomy
Prostatic Neoplasms pathology
Prostatic Neoplasms surgery
Receptors, Androgen genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 6
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 21552559
- Full Text :
- https://doi.org/10.1371/journal.pone.0019059