Constitutive β-Catenin Activation Induces Male-Specific Tumorigenesis in the Bladder Urothelium

Abstract

The incidence for bladder urothelial carcinoma (UC), a common malignancy of the urinary tract, is about three times higher in men than in women. Although this gender difference has been primarily attributed to differential exposures, it is likely that underlying biological causes contribute to the gender inequality. In this study, we report a transgenic mouse bladder tumor model upon induction of constitutively activated β-catenin signaling in the adult urothelium. We showed that the histopathology of the tumors observed in our model closely resembled that of the human low grade urothelial carcinoma. Additionally, we provided evidence supporting the KRT5-positive;KRT7-negative basal cells as the putative cells-of-origin for β-catenin-induced luminal tumor. Intriguingly, the tumorigenesis in this model demonstrated a marked difference between opposite sexes; forty percent of males developed macroscopically detectable luminal tumors in twelve weeks, whereas only three percent of females developed tumors. We investigated the mechanisms underlying this sexual dimorphism in pathogenesis and demonstrated that nuclear translocation of the androgen receptor (AR) in the urothelial cells is a critical mechanism contributing to tumor development in male mice. Finally, we performed global gene profiling experiments and defined the molecular signature for the β-catenin-induced tumorigenesis in males. Altogether, we have established a model for investigating sexual dimorphism in UC development, and implicated synergy between β-catenin signaling and androgen/AR signaling in carcinogenesis of the basal urothelial cells.

The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage

“…However, BBN is not a human bladder carcinogen. Lin et al recently reported that constitutive β-catenin activation in mouse bladder epithelium resulted in male specific bladder cancer development and that AR was a critical mediator [13]. However, abnormal β-catenin activation appears to be rare in human bladder cancer [14].…”

Urothelial generation and regeneration in development, injury, and cancer

“…Interstitial cystitis/painful bladder syndrome frequently presents with symptoms similar to those of a UTI with pelvic pain and urinary frequency or urgency, but is an idiopathic, multifactorial condition that is increasing in frequency worldwide (Davis et al, 2014). Bladder cancer is the ninth most common cancer worldwide and occurs 3 times more frequently in men than in women (Freedman et al, 2011; Lin et al, 2013; Ferlay et al, 2015; Malats and Real, 2015; Antoni et al, 2016). Due to their prevalence and largely indolent course, the economic burden of urinary tract diseases is enormous.…”

“…Van Batavia et al found that papillary tumors arise from intermediate P2 cells, whereas flat aggressive lesions like CIS, muscle-invasive tumors, and SCC of the bladder arise through transformation of KRT5-basal cells (Van Batavia et al, 2014). Lin et al provided evidence supporting the KRT5+KRT7- basal cells are the putative cells-of-origin in a transgenic mouse bladder tumor model with constitutive β-catenin expression (Lin et al, 2013). Consistent with these findings, Shin et al showed that KRT5+ basal cells, which also express Shh, are required for CIS and invasive tumor formation (Shin et al, 2014).…”

“…Lin et al used a series of mouse models with urothelium-specific gain- or loss-of-function mutations in Wnt pathway components and showed that the activation of the Wnt/β-catenin pathway is essential for promoting urothelial proliferation and differentiation (Lin et al, 2013). They revealed the opposing roles of the Wnt signaling pathway in the urothelium: the canonical Wnt/β-catenin pathway induces urothelial cell proliferation and promotes differentiation, while the non-canonical Wnt pathway maintains progenitor cells and suppresses differentiation.…”

“…Several studies using mouse models show that androgen receptor (AR) signaling is involved in regulating the sexual dimorphism in bladder tumorigenesis through its interaction with β-catenin (Miyamoto et al, 2007; Johnson et al, 2008; Li et al, 2013; Lin et al, 2013). A study by Lin et al demonstrated that overexpression of β-catenin leads to nuclear translocation of AR, which then enhances transcriptional activity, thus promoting β-catenin-induced bladder tumorigenesis (Lin et al, 2013). These studies reveal an important interaction between AR and β-catenin in promoting bladder tumorigenesis and establish useful animal models to study sex differences in bladder tumorigenesis.…”