Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice.

Daniel T Johnson,Yongfeng He,Erika Hooker,Eun-Jeong Yu,Zijie Sun,Richard Luong,Mark L Gonzalgo

doi:10.1371/journal.pone.0148851

Daniel T Johnson, Yongfeng He + Show 5 more

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Journal: PLOS ONE	Publication Date: Feb 10, 2016
Citations: 29	License type: CC BY 4.0

Affiliation: Stanford University, University of Miami

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Bladder cancer represents a significant human tumor burden, accounting for about 7.7% and 2.4% of all cancer cases in males and females, respectively. While men have a higher risk of developing bladder cancer, women tend to present at a later stage of disease and with more aggressive tumors. Previous studies have suggested a promotional role of androgen signaling in enhancing bladder cancer development. To directly assess the role of androgens in bladder tumorigenesis, we have developed a novel transgenic mouse strain, R26hARLoxP/+:Upk3aGCE/+, in which the human AR transgene is conditionally expressed in bladder urothelium. Intriguingly, both male and female R26hARLoxP/+:Upk3aGCE/+ mice display a higher incidence of urothelial cell carcinoma (UCC) than the age and sex matched control littermates in response to the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). We detect expression of the human AR transgene in CK5-positive and p63-positive basal cells in bladder urothelium. Further analyses of UCC tissues from R26hARLoxP/+:Upk3aGCE/+ mice showed that the majority of tumor cells are of urothelial basal cell origin. Positive immunostaining of transgenic AR protein was observed in the majority of tumor cells of the transgenic mice, providing a link between transgenic AR expression and oncogenic transformation. We observed an increase in Ki67 positive cells within the UCC lesions of transgenic AR mice. Manipulating endogenous androgen levels by castration and androgen supplementation directly affected bladder tumor development in male and female R26hARLoxP/+:Upk3aGCE/+ mice, respectively. Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice. This new AR transgenic mouse line mimics certain features of human bladder cancer and can be used to study bladder tumorigenesis and for drug development.

Highlights

Bladder cancer represents a significant human tumor burden, with more than 70,000 new cases of bladder cancer diagnosed in the nation annually, resulting in approximately 16,000 deaths [1]
We observed the expression of Ck5 (Fig 1E”), p63 (Fig 1F”), and CK8 (Fig 1G”) overlaid with membrane-bound green fluorescent protein (mGFP) staining suggesting that most of the cells in bladder urothelium are targeted by Upk3aGCE/+ mice [21]
We generated the R26hARLoxP/+:Upk3aGCE/+ mouse strain to directly assess the role of conditional expression of the androgen receptor (AR) in the basal and intermediate cells in bladder urothelium by BBNinduced bladder tumorigenesis

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Introduction

Bladder cancer represents a significant human tumor burden, with more than 70,000 new cases of bladder cancer diagnosed in the nation annually, resulting in approximately 16,000 deaths [1]. It accounts for about 7.7% and 2.4% of all cancer cases in males and females, respectively [1]. Decreased bladder tumor incidence has been observed in an Ar knockout mouse model (ARKO) [5, 7] It appears that there is no significant correlation between tumor grades and AR expression levels in clinical patient samples [8, 9]

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