Androgen receptor mutation in androgen-independent prostate cancer

• Project/Area Number: 23659761
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUMOTO Takahiro 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授 (70447374)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 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

Research Abstract

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.

Research Products

• [Journal Article] The androgen receptor in health and disease (2013)
  • Author(s): Matsumoto T., Sakari M., Okada M., Yokoyama A., Takahashi S., Kouzmenko A., Kato S
  • Journal Title: Annu Rev Physiol Volume: 75 Pages: 201-224
  • Peer Reviewed
• [Journal Article] The androgen receptor in health and disease (2013)
  • Author(s): Matsumoto T et al.
  • Journal Title: Annual review of physiology Volume: 75 Pages: 201-224
  • Peer Reviewed
• [Journal Article] 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 (2012)
  • Author(s): 松本高広
  • Journal Title: 遺伝子医学 MOOK Volume: 22 Pages: 242-248
• [Journal Article] Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer (2011)
  • Author(s): Takahashi S., Watanabe T., Okada M., Inoue K., Ueda T., Takada I., Watabe T., Yamamoto Y., Fukuda T., Nakamura T., Akimoto C., Fujimura T., Hoshino M., Imai Y., Metzger D., Miyazono K., Minami Y., Chambon P., Kitamura T., Matsumoto T.,Kato S
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Pages: 4938-4943
  • Peer Reviewed
• [Journal Article] Genetic impact of both sex hormones in male-typical behaviors (2011)
  • Author(s): Matsumoto T, Inoue K and Kato S
  • Journal Title: Adv Exp Med Biol Volume: 707 Pages: 125-126
  • Peer Reviewed
• [Journal Article] Essential roles of androgen signaling in wolffian duct stabilization and epididymal cell differentiation (2011)
  • Author(s): 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.
  • Journal Title: Endocrinology Volume: 152 Pages: 1640-1651
  • Peer Reviewed
• [Presentation] 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 (2013)
  • Author(s): 松本高広
  • Organizer: 第60回日本実験動物学会総会
  • Place of Presentation: つくば国際会議場（茨城県）
• [Presentation] Non-canonical Wnt signaling links to AR mutation to prostate cancer (2012)
  • Author(s): Matsumoto T
  • Organizer: 15thInternational Congress on Hormonal Steroids and Hormones & Cancer
  • Place of Presentation: Ishikawa Ongakudo, (石川県)
  • Year and Date: 2012-11-17
• [Presentation] Non-canonical Wnt signaling links AR mutation to prostate cancer (2012)
  • Author(s): Matsumoto T
  • Organizer: 15th International Congress on Hormonal Steroids and Hormones & Cancer
  • Place of Presentation: Ishikawa Ongakudo (Ishikawa)
  • Invited
• [Presentation] ステロイド受容体群を介した性ホルモンの抗不安作用 (2011)
  • Author(s): 松本高広
  • Organizer: 第19回日本ステロイドホルモン学会学術集会
  • Place of Presentation: 福岡大学(福岡県)
  • Year and Date: 2011-11-26
• [Presentation] Androgen receptor function in male and female physiology & behavior (2011)
  • Author(s): Matsumoto T
  • Organizer: 6thJAPAN-ASEAN Conference on Men's Health & Aging 2011
  • Place of Presentation: Kenchoji and Kamakur Pronce Hotel, (神奈川県)
  • Year and Date: 2011-07-02
• [Presentation] 更年期疾患に寄与するアンドロゲン中枢作用 (2011)
  • Author(s): 松本高広
  • Organizer: 第99回日本泌尿器科学会総会メンズヘルスセミナー
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-04-23
• [Presentation] ステロイド受容体群を介した性ホルモンの抗不安作用 (2011)
  • Author(s): 松本高広
  • Organizer: 第84回日本内分泌学会学術総会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2011-04-21
• [Presentation] Androgen receptor function in male and female physiology & behavior (2011)
  • Author(s): Matsumoto T
  • Organizer: 6th JAPAN-ASEAN Conference on Men’s Health & Aging(招待講演)
  • Place of Presentation: 建長寺（神奈川県）
• [Presentation] 更年期疾患に寄与するアンドロゲンの中枢作用 (2011)
  • Author(s): 松本 高広
  • Organizer: 第99回日本泌尿器科学会総会メンズヘルスセミナー2011(招待講演)
  • Place of Presentation: 名古屋国際会議場（愛知県）
• [Presentation] ステロイド受容体群を介した性ホルモンの抗不安作用 (2011)
  • Author(s): 松本 高広
  • Organizer: 第19回日本ステロイドホルモン学会学術集会(招待講演)
  • Place of Presentation: 福岡大学（福岡県）
• [Presentation] ステロイド受容体群を介した性ホルモンの抗不安作用 (2011)
  • Author(s): 松本 高広
  • Organizer: 第84回日本内分泌学会学術総会(招待講演)
  • Place of Presentation: 神戸国際会議場（兵庫県）
• [Book] 「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研究」 遺伝子医学MOOK (2012)
  • Author(s): 松本高広、加藤茂明
  • Publisher: メディカル ドゥ社
• [Book] 「卵胞形成と核内アンドロゲンレセプター」卵子学 (2011)
  • Author(s): 加藤茂明、松本高広
  • Publisher: 京都大学学術出版会