Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance
Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance
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DOI：
10.1016/s0002-9440(10)63112-4
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发表时间：
2004-01-01
影响因子：
6
通讯作者：
Gerald, WL
中科院分区：
文献类型：
--
作者：
Holzbeierlein, J;Lal, P;Gerald, WL
雄激素信号通路在前列腺癌的发生发展中起着关键作用，雄激素治疗是前列腺癌治疗的主要手段。我们在雄激素消融治疗期间对前列腺癌进行了全基因组表达分析，以确定雄激素调节的基因和耐药后差异表达的基因。在63,175个探针中，有654个在用goerelin和氟他胺治疗3个月后检测到显著的表达变化。这包括149个基因，这些基因在LNCaP细胞中雄激素停用36小时后也有差异表达。这些基因反映了在治疗的肿瘤中发生的生理变化，并包括雄激素受体的潜在直接靶点。雄激素消融抵抗肿瘤的表达谱显示，在治疗过程中检测到的许多基因表达变化不再存在，这表明在没有外源激素的情况下，雄激素反应途径重新激活。治疗耐药性与一组独特的基因的差异表达有关，这些基因反映了潜在的再激活机制。具体地说，雄激素受体和类固醇生物合成关键酶的上调表明，耐药肿瘤对雄激素的敏感性和内源性合成增加。重新激活的特定途径为耐药肿瘤的分类和靶向治疗提供了机会。
The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.