Elo J P, Kvist L, Leinonen K, Isomaa V, Henttu P, Lukkarinen O, Vihko P
Biocenter Oulu, Finland.
J Clin Endocrinol Metab. 1995 Dec;80(12):3494-500. doi: 10.1210/jcem.80.12.8530589.
Androgens are necessary for the development of prostatic cancer. The mechanisms by which the originally androgen-dependent prostatic cancer cells are relieved of the requirement to use androgen for their growth are largely unknown. The human prostatic cancer cell line LNCaP has been shown to contain a point mutation in the human androgen receptor gene (hAR), suggesting that changes in the hAR may contribute to the abnormal hormone response of prostatic cells. To search for point mutations in the hAR, we used single strand conformation polymorphism analysis and a polymerase chain reaction direct sequencing method to screen 23 prostatic cancer specimens from untreated patients, 6 prostatic cancer specimens from treated patients, and 11 benign prostatic hyperplasia specimens. One mutation was identified in DNA isolated from prostatic cancer tissue, and the mutation was also detected in the leukocyte DNA of the patient and his offspring. The mutation changed codon 726 in exon E from arginine to leucine and was a germ line mutation. The mutation we found in exon E of the hAR gene does not alter the ligand binding specificity of the AR, but the mutated receptor was activated by estradiol to a significantly greater extent than the wild-type receptor. The AR gene mutation described in this study might be one explanation for the altered biological activity of prostatic cancer.
雄激素对于前列腺癌的发展是必需的。最初依赖雄激素的前列腺癌细胞摆脱对雄激素用于生长需求的机制在很大程度上尚不清楚。已证明人前列腺癌细胞系LNCaP在人雄激素受体基因（hAR）中存在一个点突变，这表明hAR的变化可能导致前列腺细胞异常的激素反应。为了寻找hAR中的点突变，我们使用单链构象多态性分析和聚合酶链反应直接测序方法，对23例未经治疗患者的前列腺癌标本、6例经治疗患者的前列腺癌标本以及11例良性前列腺增生标本进行筛选。在从前列腺癌组织分离的DNA中鉴定出一个突变，并且在该患者及其后代的白细胞DNA中也检测到该突变。该突变将外显子E中的第726密码子从精氨酸变为亮氨酸，是一种种系突变。我们在hAR基因外显子E中发现的突变不会改变AR的配体结合特异性，但突变受体被雌二醇激活的程度明显高于野生型受体。本研究中描述的AR基因突变可能是前列腺癌生物学活性改变的一种解释。
