Stanbrough Michael, Bubley Glenn J, Ross Kenneth, Golub Todd R, Rubin Mark A, Penning Trevor M, Febbo Phillip G, Balk Steven P
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Cancer Res. 2006 Mar 1;66(5):2815-25. doi: 10.1158/0008-5472.CAN-05-4000.
Androgen receptor (AR) plays a central role in prostate cancer, and most patients respond to androgen deprivation therapies, but they invariably relapse with a more aggressive prostate cancer that has been termed hormone refractory or androgen independent. To identify proteins that mediate this tumor progression, gene expression in 33 androgen-independent prostate cancer bone marrow metastases versus 22 laser capture-microdissected primary prostate cancers was compared using Affymetrix oligonucleotide microarrays. Multiple genes associated with aggressive behavior were increased in the androgen-independent metastatic tumors (MMP9, CKS2, LRRC15, WNT5A, EZH2, E2F3, SDC1, SKP2, and BIRC5), whereas a candidate tumor suppressor gene (KLF6) was decreased. Consistent with castrate androgen levels, androgen-regulated genes were reduced 2- to 3-fold in the androgen-independent tumors. Nonetheless, they were still major transcripts in these tumors, indicating that there was partial reactivation of AR transcriptional activity. This was associated with increased expression of AR (5.8-fold) and multiple genes mediating androgen metabolism (HSD3B2, AKR1C3, SRD5A1, AKR1C2, AKR1C1, and UGT2B15). The increase in aldo-keto reductase family 1, member C3 (AKR1C3), the prostatic enzyme that reduces adrenal androstenedione to testosterone, was confirmed by real-time reverse transcription-PCR and immunohistochemistry. These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.
雄激素受体（AR）在前列腺癌中起着核心作用，大多数患者对雄激素剥夺疗法有反应，但他们最终总会复发，发展为更具侵袭性的前列腺癌，即激素难治性或雄激素非依赖性前列腺癌。为了鉴定介导这种肿瘤进展的蛋白质，使用Affymetrix寡核苷酸微阵列比较了33例雄激素非依赖性前列腺癌骨髓转移灶与22例激光捕获显微切割的原发性前列腺癌中的基因表达。在雄激素非依赖性转移瘤中，多个与侵袭性行为相关的基因表达增加（基质金属蛋白酶9、细胞周期蛋白依赖性激酶亚基2、富含亮氨酸重复序列15、无翅型MMTV整合位点家族成员5A、EZH2蛋白、E2F3转录因子、多配体聚糖1、S期激酶相关蛋白2和凋亡抑制蛋白5），而一个候选肿瘤抑制基因（Krüppel样因子6）表达降低。与去势雄激素水平一致，雄激素调节基因在雄激素非依赖性肿瘤中减少了2至3倍。尽管如此，它们仍是这些肿瘤中的主要转录本，表明雄激素受体转录活性有部分重新激活。这与雄激素受体表达增加（5.8倍）以及多个介导雄激素代谢的基因（3β-羟基类固醇脱氢酶2、醛糖还原酶家族1成员C3、5α-还原酶1、醛糖还原酶家族1成员C2、醛糖还原酶家族1成员C1和尿苷二磷酸葡萄糖醛酸基转移酶2B15）表达增加有关。通过实时逆转录聚合酶链反应和免疫组织化学证实了醛糖还原酶家族1成员C3（AKR1C3）的增加，该前列腺酶可将肾上腺雄烯二酮还原为睾酮。这些结果表明，肾上腺雄激素向睾酮和双氢睾酮的细胞内转化增强是前列腺癌细胞适应雄激素剥夺的一种机制，并提示了新的治疗靶点。
