Taplin M E, Bubley G J, Shuster T D, Frantz M E, Spooner A E, Ogata G K, Keer H N, Balk S P
Department of Medicine, University of Massachusetts Medical Center, Worcester, USA.
N Engl J Med. 1995 May 25;332(21):1393-8. doi: 10.1056/NEJM199505253322101.
Metastatic prostate cancer is a leading cause of cancer-related death in men. The rate of response to androgen ablation is high, but most patients relapse as a result of the outgrowth of androgen-independent tumor cells. The androgen receptor, which binds testosterone and stimulates the transcription of androgen-responsive genes, regulates the growth of prostate cells. We analyzed the androgen-receptor genes from samples of metastatic androgen-independent prostate cancers to determine whether mutations in the gene have a role in androgen independence.
Complementary DNA was synthesized from metastatic prostate cancers in 10 patients with androgen-independent prostate cancer, and the expression of the androgen-receptor gene was estimated by amplification with the polymerase chain reaction. Exons B through H of the gene were cloned, and mutations were identified by DNA sequencing. The functional effects of the mutations were assessed in cells transfected with mutant genes.
All androgen-independent tumors expressed high levels of androgen-receptor gene transcripts, relative to the levels expressed by an androgen-independent prostate-cancer cell line (LNCaP). Point mutations in the androgen-receptor gene were identified in metastatic cells from 5 of the 10 patients examined. One mutation was in the same codon as the mutation found previously in the androgen-independent prostate-cancer cell line. The mutations were not detected in the primary tumors from of the two patients. Functional studies of two of the mutant androgen receptors demonstrated that they could be activated by progesterone and estrogen.
Most metastatic androgen-independent prostate cancers express high levels of androgen-receptor gene transcripts. Mutations in androgen-receptor genes are not uncommon and may provide a selective growth advantage after androgen ablation.
转移性前列腺癌是男性癌症相关死亡的主要原因。对雄激素剥夺疗法的反应率很高，但大多数患者会因雄激素非依赖性肿瘤细胞的生长而复发。雄激素受体与睾酮结合并刺激雄激素反应基因的转录，调节前列腺细胞的生长。我们分析了转移性雄激素非依赖性前列腺癌样本中的雄激素受体基因，以确定该基因的突变是否在雄激素非依赖性中起作用。
从10例雄激素非依赖性前列腺癌患者的转移性前列腺癌中合成互补DNA，通过聚合酶链反应扩增来估计雄激素受体基因的表达。克隆该基因的外显子B至H，并通过DNA测序鉴定突变。在转染突变基因的细胞中评估突变的功能效应。
相对于雄激素非依赖性前列腺癌细胞系（LNCaP）表达的水平，所有雄激素非依赖性肿瘤均表达高水平的雄激素受体基因转录本。在所检测的10例患者中的5例转移性细胞中鉴定出雄激素受体基因的点突变。其中一个突变与先前在雄激素非依赖性前列腺癌细胞系中发现的突变位于同一密码子。在这两名患者的原发性肿瘤中未检测到这些突变。对两个突变雄激素受体的功能研究表明，它们可被孕酮和雌激素激活。
大多数转移性雄激素非依赖性前列腺癌表达高水平的雄激素受体基因转录本。雄激素受体基因的突变并不罕见，并可能在雄激素剥夺后提供选择性生长优势。
