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Constitutive B-Catenin Activation Induces Male-Specific

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Constitutive B-Catenin Activation Induces Male-Specific Published OnlineFirst August 8, 2013; DOI: 10.1158/0008-5472.CAN-12-4198 Cancer Molecular and Cellular Pathobiology Research Constitutive b-Catenin Activation Induces Male-Specific Tumorigenesis in the Bladder Urothelium Congxing Lin1, Yan Yin1, Kristina Stemler2, Peter Humphrey3, Adam S. Kibel4, Indira U. Mysorekar2,3, and Liang Ma1 Abstract The incidence for bladder urothelial carcinoma, 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 biologic causes contribute to the gender inequality. In this study, we report a transgenic mouse bladder tumor model upon induction of constitutively activated b-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. In addition, we provided þ À evidence supporting the KRT5-positive;KRT7-negative (KRT5 ;KRT7 ) basal cells as the putative cells-of- origin for b-catenin–induced luminal tumor. Intriguingly, the tumorigenesis in this model showed a marked difference between opposite sexes; 40% of males developed macroscopically detectable luminal tumors in 12 weeks, whereas only 3% of females developed tumors. We investigated the mechanisms underlying this sexual dimorphism in pathogenesis and showed 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 carried out global gene profiling experiments and defined the molecular signature for the b-catenin–induced tumorigenesis in males. Altogether, we have established a model for investigating sexual dimorphism in urothelial carcinoma development, and implicated synergy between b-catenin signaling and androgen/AR signaling in carcinogenesis of the basal urothelial cells. Cancer Res; 73(19); 5914–25. Ó2013 AACR. Introduction remained stable even when the smoking prevalence markedly Bladder cancer is the fourth most common cancer type increased in women (3). These observations suggested intrinsic among men, and ninth among women (1). Lifetime cost for mechanisms underpinning gender-based differential suscep- patients with bladder cancer is the highest among all cancer tibility to bladder cancer. types on a per-patient basis (2). Despite its high prevalence and The most common type of bladder cancer is urothelial burden, the etiology of bladder cancer is poorly understood. carcinoma arising from the bladder urothelium. Normally, One important feature of bladder cancer is that its incidence mature urothelium renews itself slowly but continuously by is three times higher in men than in women (1), despite the producing new cells in the basal layer, which differentiate into fact that the development and function of the bladder are intermediate cells and terminally differentiated apical umbrel- not thought to be linked to sex hormones. Historically, this la cells. However, under pathogenic conditions, the basal male predilection, similar to lung cancer, was explained by urothelial cells can rapidly proliferate to restore homeostasis higher rates of tobacco smoking in men. However, this male (4, 5). Therefore, the basal cell layer has been proposed to be the predilection existed in the nonsmoking population, and con- urothelial stem cell niche (4). Interestingly, the tumor-initiat- trary to lung cancers, the gender difference in bladder cancers ing cells isolated from urothelial carcinoma show basal cell characteristics (6, 7). However, the cells-of-origin for urothelial carcinoma remains to be determined. Abnormal activation of the canonical WNT/b-catenin path- Authors' Affiliations: 1Division of Dermatology, Department of Medicine, Departments of 2Obstetrics and Gynecology, and 3Pathology and Immu- way is implicated in many cancer types, especially those nology, Washington University in St. Louis, St. Louis, Missouri; and 4Divi- affecting epithelia of endodermal origin, such as prostate (8) sion of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts and colorectal cancers (9). Elevated WNT activity, possibly through promoter hypermethylation-mediated repression of Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). WNT inhibitors, has been reported in a subset of bladder cancers (10, 11). Moreover, augmented expression of WNT Corresponding Author: Congxing Lin, Division of Dermatology, Depart- b ment of Medicine, Washington University School of Medicine, 660 South pathway genes (6) and nuclear localization of -catenin (12) Euclid Avenue, St. Louis, MO 63110. Phone: 314-454-8283; Fax: 314-454- have been observed in the bladder tumor-initiating cells. In 5626; E-mail: [email protected] mice, WNT/b-catenin signaling is required for basal urothelial doi: 10.1158/0008-5472.CAN-12-4198 proliferation during injury-induced regeneration (13), and Ó2013 American Association for Cancer Research. forced expression of a constitutively activated form of 5914 Cancer Res; 73(19) October 1, 2013 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst August 8, 2013; DOI: 10.1158/0008-5472.CAN-12-4198 b-Catenin in Male-Specific Urothelial Tumorigenesis b-catenin using UPII-Cre caused urothelial overgrowth, medium was replaced according to the treatment plan and although no tumor developed in the absence of additional MTT assay conducted on one plate every 24 hours as pre- mutations (14, 15). Together, these observations indicate a viously described. Each treatment was carried out in triplicates dynamic role for WNT/b-catenin signaling in regulating for at least three times, and representative results were homeostasis and carcinogenesis of the urothelium. presented. Androgen and androgen receptor (AR) signaling has also been linked to bladder cancers, as AR knockout mice Luciferase assay showed resistance to N-butyl-N-(4-hydroxybutyl)nitrosamine– Bladder cancer cells were seeded on white 96-well plates induced carcinogenesis (16). Cross-talk between WNT/ (10,000 cells/well) and let attach overnight. The next day, cells b-catenin and androgen–AR pathways has been reported were transfected with canonical WNT activity reporter LEF- both during development (17) and in carcinogenesis, partic- LUC and pRL-TK vector (Promega) using X-tremeGENE ularly in prostate cancer (8, 18, 19). Notably, a recent HP (Roche Applied Science) following the manufacturer's study showed a strong association between nuclear AR and instructions. Culture media containing transfection reagent b-catenin expression in human bladder cancers (20), and was replaced 24 hours later with conditioned media and the authors further revealed an interaction between these cells were incubated for additional 48 hours. Luciferase activity two proteins in bladder cancer cell lines. These findings was measured using the Dual-Glo luciferase assay system prompted us to hypothesize that b-catenin is involved in (Promega) and relative LEF-LUC activity was calculated as mediating sexual dimorphism in bladder tumorigenesis. the ratio of luminescence from LEF-LUC (firefly luciferase) to Herein, by using an inducible transgenic system to force pRL-TK (Renilla luciferase). persistent b-catenin activation in adult urothelium, we estab- lished a mouse bladder tumor model that exhibits strong Statistical analyses male predilection as a consequence of synergy between Student t tests were conducted to compare proliferative b-catenin and androgen/AR signaling. indices between experimental groups. Additional information is available in the Supplementary Materials and Methods Methods. Animal maintenance All animals were housed in the animal facility at Washing- Results ton University (St. Louis, MO) according to NIH (Bethesda, Forced expression of stabilized b-catenin in mature MD) and Animal Care and Use Committee guidelines. Doxy- urothelium induced luminal bladder tumors in male cycline food pellets 200 mg/kg were purchased from Bio- mice Serv. Castration was carried out following standard surgical Previousstudieshaveinvestigatedtheroleforsustained procedures. b-catenin activation in the urothelium by using a urothelial- specific UPII-Cre (14, 15). However, the urothelial expression Histologic analyses of this Cre is patchy and restricted to the upper layer of Bisected bladder were embedded in paraffin or optimum differentiated cells; the basal layer, which contains progeni- cutting temperature and cut into 5 mm sections. Immunohis- tor cells that have high proliferative reserve and therefore tochemical and immunofluorescence stainings were con- are more likely to be the cells-of-origin for tumors, is largely ducted according to standard protocols. excluded (Fig. 3C, b–d in ref. 21). Importantly, the basal layer is also the endogenous site of WNT activation during RNA isolation, microarray analysis, and real-time injury-induced regeneration. Therefore, we sought to use reverse transcriptase PCR an alternative genetic tool that can target basal urothelial The urothelium was physically separated from the bladder cells with high efficiency. We adopted an Msx2rtTA;tetO-Cre for RNA extraction using the RNeasy Kit (Qiagen). Illumina system, which confers Cre expression in Msx2-expressing mouse-6 chips were used for microarray analysis. cells upon doxycycline
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