Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Res. 2012 Dec 1;72(23):6142-52. doi: 10.1158/0008-5472.CAN-12-1335. Epub 2012 Sep 12.
Androgen receptor (AR) signaling persists in castration-resistant prostate carcinomas (CRPC), because of several mechanisms that include increased AR expression and intratumoral androgen metabolism. We investigated the mechanisms underlying aberrant expression of transcripts involved in androgen metabolism in CRPC. We compared gene expression profiles and DNA copy number alteration (CNA) data from 29 normal prostate tissue samples, 127 primary prostate carcinomas (PCa), and 19 metastatic PCas. Steroidogenic enzyme transcripts were evaluated by quantitative reverse transcriptase PCR in PCa cell lines and circulating tumor cells (CTC) from CRPC patients. Metastatic PCas expressed higher transcript levels for AR and several steroidogenic enzymes, including SRD5A1, SRD5A3, and AKR1C3, whereas expression of SRD5A2, CYP3A4, CYP3A5, and CYP3A7 was decreased. This aberrant expression was rarely associated with CNAs. Instead, our data suggest distinct patterns of coordinated aberrant enzyme expression. Inhibition of AR activity by itself stimulated AKR1C3 expression. The aberrant expression of the steroidogenic enzyme transcripts was detected in CTCs from CRPC patients. In conclusion, our findings identify substantial interpatient heterogeneity and distinct patterns of dysregulated expression of enzymes involved in intratumoral androgen metabolism in PCa. These steroidogenic enzymes represent targets for complete suppression of systemic and intratumoral androgen levels, an objective that is supported by the clinical efficacy of the CYP17 inhibitor abiraterone. A comprehensive AR axis-targeting approach via simultaneous, frontline enzymatic blockade, and/or transcriptional repression of several steroidogenic enzymes, in combination with GnRH analogs and potent antiandrogens, would represent a powerful future strategy for PCa management.
雄激素受体（AR）信号在去势抵抗性前列腺癌（CRPC）中持续存在，这是由于包括 AR 表达增加和肿瘤内雄激素代谢在内的几种机制。我们研究了导致 CRPC 中与雄激素代谢相关的转录本异常表达的机制。我们比较了 29 份正常前列腺组织样本、127 例原发性前列腺癌（PCa）和 19 例转移性 PCa 的基因表达谱和 DNA 拷贝数改变（CNA）数据。在 PCa 细胞系和 CRPC 患者的循环肿瘤细胞（CTC）中，我们通过定量逆转录 PCR 评估了类固醇生成酶的转录本。转移性 PCa 表达了更高水平的 AR 和几种类固醇生成酶的转录本，包括 SRD5A1、SRD5A3 和 AKR1C3，而 SRD5A2、CYP3A4、CYP3A5 和 CYP3A7 的表达则降低。这种异常表达很少与 CNA 相关。相反，我们的数据表明存在协调异常酶表达的不同模式。AR 活性的抑制本身就刺激了 AKR1C3 的表达。在 CRPC 患者的 CTC 中检测到了这些类固醇生成酶转录本的异常表达。总之，我们的发现确定了 PCa 中肿瘤内雄激素代谢相关酶的表达失调存在显著的个体间异质性和不同模式。这些类固醇生成酶代表了完全抑制全身和肿瘤内雄激素水平的目标，CYP17 抑制剂阿比特龙的临床疗效支持这一目标。通过同时进行的一线酶阻断和/或几种类固醇生成酶的转录抑制，以及 GnRH 类似物和有效的抗雄激素药物，对 AR 轴进行全面靶向治疗，将是 PCa 管理的一项强大的未来策略。
