Noncanonical Wnt Signaling Mediates Androgen-dependent Tumor Growth in a Mouse Model of Prostate Cancer

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2011 Mar 9

PMID 21383160

Citations 30

Authors

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 Matsumoto

Shigeaki Kato

Affiliations

Soon will be listed here.

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.

Citing Articles

Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/β-catenin signaling pathway.

Zhang X, Li H, Wang Y, Zhao H, Wang Z, Chan F Cell Death Dis. 2024; 15(3):234.

PMID: 38531859 PMC: 10965960. DOI: 10.1038/s41419-024-06621-w.

Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability.

Perez Baca M, Jacobs E, Vantomme L, LeBlanc P, Bogaert E, Dheedene A Am J Hum Genet. 2024; 111(3):509-528.

PMID: 38412861 PMC: 10940049. DOI: 10.1016/j.ajhg.2024.01.013.

ESS2 controls prostate cancer progression through recruitment of chromodomain helicase DNA binding protein 1.

Takahashi S, Takada I, Hashimoto K, Yokoyama A, Nakagawa T, Makishima M Sci Rep. 2023; 13(1):12355.

PMID: 37524814 PMC: 10390525. DOI: 10.1038/s41598-023-39626-0.

Bioengineered BERA-Wnt5a siRNA Targeting Wnt5a/FZD2 Signaling Suppresses Advanced Prostate Cancer Tumor Growth and Enhances Enzalutamide Treatment.

Ning S, Liu C, Lou W, Yang J, Lombard A, DAbronzo L Mol Cancer Ther. 2022; 21(10):1594-1607.

PMID: 35930737 PMC: 9547958. DOI: 10.1158/1535-7163.MCT-22-0216.

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer.

Koushyar S, Meniel V, Phesse T, Pearson H Biomolecules. 2022; 12(2).

PMID: 35204808 PMC: 8869457. DOI: 10.3390/biom12020309.

References

Jia L, Berman B, Jariwala U, Yan X, Cogan J, Walters A . Genomic androgen receptor-occupied regions with different functions, defined by histone acetylation, coregulators and transcriptional capacity. PLoS One. 2008; 3(11):e3645. PMC: 2577007. DOI: 10.1371/journal.pone.0003645. View

Pukrop T, Binder C . The complex pathways of Wnt 5a in cancer progression. J Mol Med (Berl). 2007; 86(3):259-66. DOI: 10.1007/s00109-007-0266-2. View

Sanjo H, Takeda K, Tsujimura T, Ninomiya-Tsuji J, Matsumoto K, Akira S . TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling. Mol Cell Biol. 2003; 23(4):1231-8. PMC: 141141. DOI: 10.1128/MCB.23.4.1231-1238.2003. View

Brinkmann A, Trapman J . Prostate cancer schemes for androgen escape. Nat Med. 2000; 6(6):628-9. DOI: 10.1038/76194. View

Chen C, Welsbie D, Tran C, Baek S, Chen R, Vessella R . Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004; 10(1):33-9. DOI: 10.1038/nm972. View

Norris J, Chang C, Wittmann B, Kunder R, Cui H, Fan D . The homeodomain protein HOXB13 regulates the cellular response to androgens. Mol Cell. 2009; 36(3):405-16. PMC: 2788777. DOI: 10.1016/j.molcel.2009.10.020. View

Takada I, Mihara M, Suzawa M, Ohtake F, Kobayashi S, Igarashi M . A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol. 2007; 9(11):1273-85. DOI: 10.1038/ncb1647. View

Shay J, Wright W . Telomerase: a target for cancer therapeutics. Cancer Cell. 2002; 2(4):257-65. DOI: 10.1016/s1535-6108(02)00159-9. View

Yoshida T, Kinoshita H, Segawa T, Nakamura E, Inoue T, Shimizu Y . Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. Cancer Res. 2005; 65(21):9611-6. DOI: 10.1158/0008-5472.CAN-05-0817. View

10.

Lilja H, Ulmert D, Vickers A . Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer. 2008; 8(4):268-78. DOI: 10.1038/nrc2351. View

11.

Veeman M, Axelrod J, Moon R . A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell. 2003; 5(3):367-77. DOI: 10.1016/s1534-5807(03)00266-1. View

12.

Lei Q, Jiao J, Xin L, Chang C, Wang S, Gao J . NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss. Cancer Cell. 2006; 9(5):367-78. DOI: 10.1016/j.ccr.2006.03.031. View

13.

Katoh M, Katoh M . STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review). Int J Mol Med. 2007; 19(2):273-8. View

14.

. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet. 2000; 355(9214):1491-8. View

15.

Mooradian A, Morley J, Korenman S . Biological actions of androgens. Endocr Rev. 1987; 8(1):1-28. DOI: 10.1210/edrv-8-1-1. View

16.

De Marzo A, Platz E, Sutcliffe S, Xu J, Gronberg H, Drake C . Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7(4):256-69. PMC: 3552388. DOI: 10.1038/nrc2090. View

17.

Glass C, Rosenfeld M . The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000; 14(2):121-41. View

18.

Taplin M, Bubley G, Shuster T, FRANTZ M, Spooner A, Ogata G . Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995; 332(21):1393-8. DOI: 10.1056/NEJM199505253322101. View

19.

Zhu P, Baek S, Bourk E, Ohgi K, Garcia-Bassets I, Sanjo H . Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell. 2006; 124(3):615-29. DOI: 10.1016/j.cell.2005.12.032. View

20.

Sun C, Shi Y, Xu L, Nageswararao C, Davis L, Segawa T . Androgen receptor mutation (T877A) promotes prostate cancer cell growth and cell survival. Oncogene. 2006; 25(28):3905-13. DOI: 10.1038/sj.onc.1209424. View