MUTATED HUMAN ANDROGEN RECEPTOR GENE DETECTED IN A PROSTATIC-CANCER PATIENT IS ALSO ACTIVATED BY ESTRADIOL
MUTATED HUMAN ANDROGEN RECEPTOR GENE DETECTED IN A PROSTATIC-CANCER PATIENT IS ALSO ACTIVATED BY ESTRADIOL
复制标题
DOI：
10.1210/jc.80.12.3494
复制
发表时间：
1995-12-01
影响因子：
5.8
通讯作者：
VIHKO, P
中科院分区：
文献类型：
--
作者：
ELO, JP;KVIST, L;VIHKO, P
雄激素是前列腺癌发生发展所必需的。最初依赖雄激素的前列腺癌细胞不需要使用雄激素来生长的机制在很大程度上是未知的。人前列腺癌LNCaP细胞系中含有人雄激素受体基因(HAR)的点突变，提示HAR基因的突变可能与前列腺细胞的激素反应异常有关。为了寻找HAR基因的点突变，我们采用单链构象多态性分析和聚合酶链式反应直接测序的方法，对23例前列腺癌初治患者、6例前列腺癌治疗患者和11例良性前列腺增生症患者进行了筛查。从前列腺癌组织中提取的DNA中检测到1例突变，该突变也在患者及其后代的白细胞DNA中检测到。该突变使外显子E的726位密码子从精氨酸变为亮氨酸，是一种生殖系突变。我们在HAR基因外显子E上发现的突变并不改变AR的配体结合特异性，但突变的受体被雌激素激活的程度明显高于野生型受体。本研究描述的AR基因突变可能是前列腺癌生物学活性改变的一种解释。
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 wildtype receptor.The AR gene mutation described in this study might be one explanation for the altered biological activity of prostatic cancer.