Fiche publication


Date publication

mars 2011

Auteurs

Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre , Dr METZGER Daniel


Tous les auteurs :
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

Résumé

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.

Référence

Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4938-43