Androgen receptor mutation in androgen-independent prostate cancer

前列腺癌的发生与过度活跃的雄激素信号有关。然而，雄激素受体(AR)功能与体液因子之间的分子联系仍不清楚。通过Cre-ERT2介导的靶向性体细胞突变，在前列腺癌上皮细胞中选择性地将AR苏氨酸877突变为丙氨酸，从而建立前列腺癌小鼠模型。这种AR点突变小鼠(ARPE-T877A/Y)出现肥大的前列腺，对雄激素拮抗剂和雌激素都有反应，尽管没有发现前列腺癌。在前列腺癌模型转基因小鼠中，通过将AR T877A突变引入前列腺癌中，前列腺癌的发生以及肿瘤的生长显著增强。对小鼠的基因筛查证明WNT-5a是一种激活剂。WNT-5a在恶性前列腺癌中表达增强，而在良性前列腺增生症中表达上调不明显。这些发现表明，非规范的Wnt信号刺激了AR功能亢进的前列腺癌的发展。

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.