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。恶性前列腺癌患者中Wnt-5a表达增强，而良性前列腺增生患者中Wnt-5a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。

项目成果

Genetic impact of both sex hormones in male-typical behaviors.

两种性激素对男性典型行为的遗传影响。

• 发表时间: 2011
• 期刊: Advances in Experimental Medicine and Biology
• 作者: Takahiro Matsumoto;Kazuki Inoue;Takashi Sato;S. Kato
• 通讯作者: S. Kato

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

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