MP88-08 ESTROGEN RECEPTOR (ER)-β SIGNALS INDUCE UROTHELIAL TUMORIGENESIS VIA DOWN-REGULATION OF A POTENTIAL TUMOR SUPPRESSOR FORKHEAD BOX PROTEIN O1 (FOXO1)

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You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP88-08 ESTROGEN RECEPTOR (ER)-β SIGNALS INDUCE UROTHELIAL TUMORIGENESIS VIA DOWN-REGULATION OF A POTENTIAL TUMOR SUPPRESSOR FORKHEAD BOX PROTEIN O1 (FOXO1) Hiroki Ide, Satoshi Inoue, Kazutoshi Fujita, Yi Li, Takashi Kawahara, Eiji Kashiwagi, Taichi Mizushima, Seiji Yamaguchi, Hiroaki Fushimi, Mototsugu Oya, Norio Nonomura, and Hiroshi Miyamoto Hiroki IdeHiroki Ide More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Kazutoshi FujitaKazutoshi Fujita More articles by this author , Yi LiYi Li More articles by this author , Takashi KawaharaTakashi Kawahara More articles by this author , Eiji KashiwagiEiji Kashiwagi More articles by this author , Taichi MizushimaTaichi Mizushima More articles by this author , Seiji YamaguchiSeiji Yamaguchi More articles by this author , Hiroaki FushimiHiroaki Fushimi More articles by this author , Mototsugu OyaMototsugu Oya More articles by this author , Norio NonomuraNorio Nonomura More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2733AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent preclinical evidence suggests the involvement of ER signaling in urothelial tumorigenesis, although its underlying mechanisms remain unclear. Meanwhile, cross-talk between FOXO1, a transcriptional factor known to induce apoptosis through the PI3K-Akt pathway, and ERβ has been demonstrated in prostate cancer cells. We therefore investigated the role of FOXO1 in neoplastic transformation of urothelial cells in relation to ERβ signaling. METHODS We immunohistochemically stained for ERβ and phospho-FOXO1 (p-FOXO1), an inactive form of FOXO1, in the tissue microarrays consisting of 99 cases of upper urinary tract urothelial carcinoma and paired non-neoplastic urothelium. Then, in ERα(-)/ERβ(+) human normal urothelial SVHUC sublines stably expressing control- or FOXO1-shRNA with or without exposure to a chemical carcinogen 3-methylcholanthrene (MCA), we assessed the expression of FOXO1 and other known tumor suppressors (via RT-PCR and western blot) as well as neoplastic transformation (via MTT assay and mouse xenograft model). RESULTS ERβ and p-FOXO1 were positive in 63% and 100% of urothelial tumors, which were significantly lower and higher than in non-neoplastic urothelial tissues [85% (P=0.001) and 94% (P=0.018)], respectively. In addition, there was a significant correlation between strong (3+) p-FOXO1 expression and ERβ positivity (P=0.002). In SVHUC cells, estradiol reduced FOXO1 expression, which was abolished by an anti-estrogen tamoxifen. FOXO1 knockdown considerably accelerated neoplastic transformation of MCA-SVHUC cells. Moreover, the expression levels of several genes known to inhibit urothelial carcinogenesis (e.g. p21, p27, UGT1A) were significantly lower in MCA-SVHUC-FOXO1-shRNA than in control cells. Notably, tamoxifen treatment resulted in inhibition of neoplastic transformation of control cells, which was abolished by a FOXO1 inhibitor AS1842856. However, no significant effects of tamoxifen on neoplastic transformation were seen in MCA-SVHUC-FOXO1-shRNA cells. CONCLUSIONS FOXO1 appeared to function as a tumor suppressor and could strongly prevent urothelial tumorigenesis. In contrast, ERβ signals were found to promote it presumably via down-regulation of FOXO1 expression. Accordingly, FOXO1 stimulation via an activator, together with ERβ inactivation via an anti-estrogen, has the potential of being an effective chemopreventive approach for urothelial carcinoma. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1177 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hiroki Ide More articles by this author Satoshi Inoue More articles by this author Kazutoshi Fujita More articles by this author Yi Li More articles by this author Takashi Kawahara More articles by this author Eiji Kashiwagi More articles by this author Taichi Mizushima More articles by this author Seiji Yamaguchi More articles by this author Hiroaki Fushimi More articles by this author Mototsugu Oya More articles by this author Norio Nonomura More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...