Content area
Full Text
Oncogene (2016) 35, 702714 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16
www.nature.com/onc
ORIGINAL ARTICLE
Androgen signaling is a confounding factor for -catenin-mediated prostate tumorigenesis
SH Lee1, R Luong2, DT Johnson1, GR Cunha3, L Rivina1, ML Gonzalgo1 and Z Sun1
Emerging evidence has demonstrated the critical roles for both androgen and Wnt pathways in prostate tumorigenesis. A recent integrative genomic analysis of human prostate cancers (PCas) has revealed a unique enrichment of androgen and Wnt signaling in early-onset PCas, implying their clinical signicance in the disease. Additionally, interaction between the androgen receptor (AR) and -catenin has long been detected in PCa cells. However, the consequence of this interaction in prostate tumorigenesis is still unknown. Because mutations in adenomatous polyposis coli, -catenin and other components of the destruction complex are generally rare in PCas, other mechanisms of aberrant Wnt signaling activation have been speculated. To address these critical questions, we developed Ctnnb1L(ex3)/+/R26hARL/+:PB-Cre4 mice, in which transgenic AR and stabilized -catenin are co-expressed in
prostatic epithelial cells. We observed accelerated tumor development, aggressive tumor invasion and a decreased survival rate in Ctnnb1L(ex3)/+/R26hARL/+:PB-Cre4 compound mice compared with age-matched Ctnnb1L(ex3)/+:PB-Cre4 littermate controls, which only
have stabilized -catenin expression in the prostate. Castration of the above transgenic mice resulted in signicant tumor regression, implying an essential role of androgen signaling in tumor growth and maintenance. Implantation of the prostatic epithelial cells isolated from the transgenic mice regenerated prostate intraepithelial neoplasias and prostatic adenocarcinoma lesions. Microarray analyses of transcriptional proles showed more robust enrichment of known tumor- and metastasis-promoting genes: Spp1, Egr1, c-Myc, Sp5, and Sp6 genes, in samples isolated from Ctnnb1L(ex3)/+/R26hARL/+:PB-Cre4 compound mice than those
from Ctnnb1L(ex3)/+:PB-Cre4 and R26hARL/+:PB-Cre4 littermate controls. Together, these data demonstrate a confounding role of
androgen signaling in -catenin-initiated oncogenic transformation in prostate tumorigenesis.
Oncogene (2016) 35, 702714; doi:10.1038/onc.2015.117; published online 20 April 2015
INTRODUCTIONAndrogen signaling, mediated through the androgen receptor (AR) and its ligands, testosterone and 5-dihydrotestosterone, is essential for prostate tumorigenesis.13 Androgen-deprivation therapy inhibits androgen signaling-mediated cell growth and survival and thus has been widely used to treat prostate cancer (PCa).4 The AR is expressed in most PCa samples before and after the therapy.5 In fact, AR gene amplication appears in one-third of PCa samples after androgen-deprivation therapy.6 Additionally, global gene-expression proling shows that...