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

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.

authors

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

doi

10.1073/pnas.1014850108

subject

Has Abstract

pub_date

2011-03-22 00:00:00

pages

4938-43

issue

12

eissn

0027-8424

issn

1091-6490

pii

1014850108

journal_volume

108

pub_type

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