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

Sayuri Takahashi, Tomoyuki Watanabe, Maiko Okada, Kazuki Inoue, Takashi Ueda, Ichiro Takada, Tetsuro Watabe, Yoko Yamamoto, Toru Fukuda, Takashi Nakamura, Chihiro Akimoto, Tetsuya Fujimura, Maiko Hoshino, Yuuki Imai, Daniel Metzger, Kohei Miyazono, Yasuhiro Minami, Pierre Chambon, Tadaichi Kitamura, Takahiro MatsumotoShigeaki Kato

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)4938-4943
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number12
DOIs
Publication statusPublished - 2011 Mar 22
Externally publishedYes

Keywords

  • Antiandrogen
  • Hormone-refractory state
  • TRAMP

ASJC Scopus subject areas

  • General

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