Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer-猫眼课题宝

DOI：

10.1073/pnas.1014850108

发表时间：

2011-03

期刊：

Proceedings of the National Academy of Sciences

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Sayuri Takahashi;Tomoyuki Watanabe;Maiko Okada;Kazuki Inoue;T. Ueda;I. Takada;T. Watabe;Yoko Yamamoto;T. Fukuda;Takashi Nakamura;Chihiro Akimoto;T. Fujimura;Maiko Hoshino;Yuuki Imai;D. Metzger;K. Miyazono;Y. Minami;P. Chambon;T. Kitamura;Takahiro Matsumoto;S. Kato

前列腺癌的发展与雄激素信号过度活跃有关。然而，雄激素受体（AR）功能与体液因子之间的分子联系尚不清楚。通过cre - ert2介导的靶向体细胞诱变，将前列腺上皮细胞中的AR苏氨酸877选择性突变为丙氨酸，建立前列腺癌小鼠模型。这种AR点突变小鼠（ARpe-T877A/Y）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 T877A突变引入前列腺，可以显著增强前列腺肿瘤发生的发生和肿瘤的生长。小鼠遗传筛选鉴定Wnt-5a为激活剂。Wnt-5a在恶性前列腺肿瘤中表达增强，而在良性前列腺增生中表达异常上调不明显。这些发现提示非典型Wnt信号刺激伴有AR功能亢进的前列腺肿瘤的发展。

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 prostatic 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 tumors of patients, whereas in benign 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.

Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer

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