Androgen receptor mutation in androgen-independent prostate cancer

前列腺癌的发生与雄激素信号过度活跃有关。然而，雄激素受体（AR）功能和体液因子之间的分子联系仍然难以捉摸。通过Cre-ERT 2介导的靶向体细胞诱变，在前列腺上皮细胞中将AR苏氨酸877选择性突变为丙氨酸，产生前列腺癌小鼠模型。这种AR点突变小鼠（ARpe-T877 A/Y）出现肥大前列腺，对雄激素拮抗剂和雌激素均有反应，但未见前列腺肿瘤。在前列腺癌模型转基因小鼠中，通过将AR T877 A突变引入前列腺，前列腺肿瘤发生的发生以及肿瘤生长显著增强。小鼠的遗传筛选鉴定Wnt-5a为激活剂。Wnt-5a在恶性前列腺癌中表达增强，而在良性前列腺增生中表达不明显。这些发现表明，非经典的Wnt信号刺激前列腺肿瘤的发展与AR功能亢进。

Prostate cancer development is associated with hyperactive androgen signaling. However, the molecular link between androgen receptor (AR) function and humoral factors remains elusive. A prostate cancer mouse model was generated by selectively mutating the AR threonine 877 into alanine in proatatic epithelial cells through Cre-ERT2-mediated targeted somatic mutagenesis. Such AR point mutant mice (ARpe-T877A/Y) developed hypertrophic prostates with responses to both an androgen antagonist and estrogen, although no prostatic tumor was seen. In prostate cancer model transgenic mice, the onset of prostatic tumorigenesis as well as tumor growth was significantly potentiated by introduction of the AR T877A mutation into the prostate. Genetic screening of mice identified Wnt-5a as an activator. Enhanced Wnt-5a expression was detected in the malignant prostate cancers of patients, whereas in benigh prostatic hyperplasia such aberrant up-regulation was not obvious. These findings suggest that a noncanonical Wnt signal stimulates development of prostatic tumors with AR hyperfunction.