Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
PLoS One. 2011 Apr 28;6(4):e19059. doi: 10.1371/journal.pone.0019059.
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-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.
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.
缺乏配体结合域（LBD）的组成性激活雄激素受体变体（AR-V）可能促进去势抵抗性前列腺癌（CRPC）的发展。然而，在临床上最重要的转移部位——骨骼中，AR-Vs 的表达尚未得到很好的记录。因此，我们的目的是比较激素-naive（HN）和 CRPC 骨转移与原发性 PC 和非恶性前列腺组织中 AR-Vs 的水平，以及与 AR 蛋白表达、全基因组转录谱和患者生存的关系。
方法/主要发现：在转移手术中从 40 名患者中获得了 10 例激素-naïve（HN）和 30 例 CRPC 骨转移样本。从 13 例前列腺切除的男性中获得了非恶性和恶性前列腺样本。使用 RT-PCR 测量全长 AR（ARfl）和 AR-Vs 称为 AR-V1、AR-V7 和 AR-V567es mRNA 的水平，并使用 Illumina Beadchip 阵列测量全基因组转录谱。通过 Western 印迹和免疫组织化学检查蛋白质水平。在大多数原发性肿瘤和转移瘤中检测到 ARfl、AR-V1 和 AR-V7 的转录物，并且在 CRPC 骨转移瘤中水平显着增加。仅在 23%的 CRPC 骨转移瘤中检测到 AR-V567es 转录物。CRPC 骨转移瘤的亚组以与 ARfl 相当的水平表达 LBD 截断的 AR 蛋白。在所有 CRPC 骨转移瘤的 1/3 中看到的上四分位数中可检测到 AR-V567es 和/或 AR-V7 mRNA 与核 AR 免疫染色评分高、细胞周期调节紊乱和生存时间短有关。
结论/意义：与 HN 骨转移相比，CRPC 中 AR-Vs 的表达增加，并与特别差的预后相关。需要进一步的研究来测试在其骨转移中表达这些 AR-Vs 的患者是否从作用于这些 AR-Vs 或下游的药物中受益更多，而不是从抑制雄激素合成的治疗中受益。
