Androgen receptor mutation in androgen-independent prostate cancer

雄激素非依赖性前列腺癌中的雄激素受体突变

• 批准号: 23659761
• 负责人: MATSUMOTO Takahiro
• 金额: $ 2.33万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659761/
• 关键词: アンドロロジー; 前立腺癌; 男性ホルモン; 抗アンドロゲン剤; ホルモン抵抗性; Wnt5a; AR; アンドロゲン受容体; 点変異

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.

前列腺癌的发展与多活跃的雄激素信号传导有关。但是，雄激素受体（AR）功能与体液因子之间的分子联系仍然难以捉摸。通过选择性地通过CRE-ERT2介导的靶向的体细胞诱变将AR苏氨酸877突变为丙氨酸的AR苏氨酸877通过选择性突变为丙氨酸，从而产生前列腺癌小鼠模型。这种AR点突变小鼠（ARPE-T877A/Y）发展出对雄激素拮抗剂和雌激素的反应，尽管没有看到前列腺肿瘤。在前列腺癌模型转基因小鼠中，前列腺肿瘤发生以及肿瘤生长的发作通过将AR T877A突变引入前列腺而显着增强。小鼠的基因筛查将Wnt-5a鉴定为激活剂。在患者的恶性前列腺癌中检测到WNT-5A的增强表达，而在贝尼前列腺增生中，这种异常上调的上调并不明显。这些发现表明，非规范的Wnt信号刺激具有AR功能超功能的前列腺肿瘤的发展。

项目成果

Non-canonical Wnt signaling links AR mutation to prostate cancer

非经典 Wnt 信号传导将 AR 突变与前列腺癌联系起来

• 发表时间: 2012
• 作者: Murashima A;Miyagawa S;Ogino Y;Nishida-Fukuda H;Araki K;Matsumoto T;Kaneko T;Yoshinaga K;Yamamura K;Kurita T;Kato S;Moon AM and Yamada G.;松本高広;Matsumoto T;Matsumoto T
• 通讯作者: Matsumoto T

ホルモン療法耐性前立腺がんモデルマウスを用いた前立腺がんの増殖亢進の分子メカニズムの解明および創薬応用研究

利用激素治疗抵抗性前列腺癌模型小鼠阐明前列腺癌生长加速的分子机制及药物发现的应用研究

• 发表时间: 2012
• 期刊: 遺伝子医学 MOOK
• 作者: Matsumoto T.;Sakari M.;Okada M.;Yokoyama A.;Takahashi S.;Kouzmenko A.;Kato S;Matsumoto T et al.;松本高広
• 通讯作者: 松本高広

ホルモン療法耐性前立腺癌の進行を司る新たな癌増悪因子「Wnt5a」の同定

鉴定出控制激素治疗耐药性前列腺癌进展的新癌症恶化因子“Wnt5a”

• 发表时间: 2013
• 作者: Murashima A;Miyagawa S;Ogino Y;Nishida-Fukuda H;Araki K;Matsumoto T;Kaneko T;Yoshinaga K;Yamamura K;Kurita T;Kato S;Moon AM and Yamada G.;松本高広
• 通讯作者: 松本高広

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

• DOI: 10.1073/pnas.1014850108
• 发表时间: 2011-03
• 期刊: Proceedings of the National Academy of Sciences
• 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

ステロイド受容体群を介した性ホルモンの抗不安作用

类固醇受体介导的性激素的抗焦虑作用

• 发表时间: 2011
• 作者: Murashima A;Miyagawa S;Ogino Y;Nishida-Fukuda H;Araki K;Matsumoto T;Kaneko T;Yoshinaga K;Yamamura K;Kurita T;Kato S;Moon AM and Yamada G.;松本高広;Matsumoto T;Matsumoto T;松本高広
• 通讯作者: 松本高広