PMID- 32031965
OWN - NLM
STAT- MEDLINE
DCOM- 20210721
LR  - 20210721
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Linking)
VI  - 27
IP  - 4
DP  - 2020 Apr
TI  - FOXO1 as a tumor suppressor inactivated via AR/ERbeta signals in urothelial cells.
PG  - 231-244
LID - 10.1530/ERC-20-0004 [doi]
AB  - Androgen receptor (AR) and estrogen receptor-beta (ERbeta) have been implicated in 
      urothelial tumor outgrowth as promoters, while underlying mechanisms remain 
      poorly understood. Our transcription factor profiling previously performed 
      identified FOXO1 as a potential downstream target of AR in bladder cancer cells. 
      We here investigated the functional role of FOXO1 in the development and 
      progression of urothelial cancer in relation to AR and ERbeta signals. In 
      non-neoplastic urothelial SVHUC cells or bladder cancer lines, AR/ERbeta expression 
      or dihydrotestosterone/estradiol treatment reduced the expression levels of FOXO1 
      gene and induced those of a phosphorylated inactive form of FOXO1 (p-FOXO1). In 
      chemical carcinogen-induced models, FOXO1 knockdown via shRNA or inhibitor 
      treatment resulted in considerable induction of the neoplastic transformation of 
      urothelial cells or bladder cancer development in mice. Similarly, FOXO1 
      inhibition considerably induced the viability, migration, and invasion of bladder 
      cancer cells. Importantly, in FOXO1 knockdown sublines, an anti-androgen 
      hydroxyflutamide or an anti-estrogen tamoxifen did not significantly inhibit the 
      neoplastic transformation of urothelial cells, while dihydrotestosterone or 
      estradiol did not significantly promote the proliferation or migration of 
      urothelial cancer cells. In addition, immunohistochemistry in surgical specimens 
      showed that FOXO1 and p-FOXO1 expression was down-regulated and up-regulated, 
      respectively, in bladder tumor tissues, which was further associated with worse 
      patient outcomes. AR or ERbeta activation is thus found to correlate with 
      inactivation of FOXO1 which appears to be their key downstream effector. 
      Moreover, FOXO1, as a tumor suppressor, is likely inactivated in bladder cancer, 
      which contributes in turn to inducing urothelial carcinogenesis and cancer 
      growth.
FAU - Ide, Hiroki
AU  - Ide H
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
AD  - Department of Urology, Keio University School of Medicine, Tokyo, Japan.
FAU - Mizushima, Taichi
AU  - Mizushima T
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
AD  - James P. Wilmot Cancer Institute, University of Rochester Medical Center, 
      Rochester, New York, USA.
FAU - Jiang, Guiyang
AU  - Jiang G
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
AD  - James P. Wilmot Cancer Institute, University of Rochester Medical Center, 
      Rochester, New York, USA.
FAU - Goto, Takuro
AU  - Goto T
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
AD  - James P. Wilmot Cancer Institute, University of Rochester Medical Center, 
      Rochester, New York, USA.
FAU - Nagata, Yujiro
AU  - Nagata Y
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
AD  - James P. Wilmot Cancer Institute, University of Rochester Medical Center, 
      Rochester, New York, USA.
FAU - Teramoto, Yuki
AU  - Teramoto Y
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
AD  - James P. Wilmot Cancer Institute, University of Rochester Medical Center, 
      Rochester, New York, USA.
FAU - Inoue, Satoshi
AU  - Inoue S
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
AD  - James P. Wilmot Cancer Institute, University of Rochester Medical Center, 
      Rochester, New York, USA.
FAU - Li, Yi
AU  - Li Y
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
FAU - Kashiwagi, Eiji
AU  - Kashiwagi E
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
FAU - Baras, Alexander S
AU  - Baras AS
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
FAU - Netto, George J
AU  - Netto GJ
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
AD  - Department of Pathology, University of Alabama at Birmingham, Birmingham, 
      Alabama, USA.
FAU - Kawahara, Takashi
AU  - Kawahara T
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
FAU - Miyamoto, Hiroshi
AU  - Miyamoto H
AD  - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland, USA.
AD  - James Buchanan Brady Urological Institute, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland, USA.
AD  - Department of Pathology & Laboratory Medicine, University of Rochester Medical 
      Center, Rochester, New York, USA.
AD  - James P. Wilmot Cancer Institute, University of Rochester Medical Center, 
      Rochester, New York, USA.
AD  - Department of Urology, University of Rochester Medical Center, Rochester, New 
      York, USA.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Estrogen Receptor beta)
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Receptors, Androgen)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Estrogen Receptor beta/*genetics
MH  - Forkhead Box Protein O1/*metabolism
MH  - Humans
MH  - Receptors, Androgen/*metabolism
MH  - Urothelium/*metabolism
OTO - NOTNLM
OT  - FOXO1
OT  - androgen receptor
OT  - estrogen receptor-beta
OT  - urothelial cancer
EDAT- 2020/02/08 06:00
MHDA- 2021/07/22 06:00
CRDT- 2020/02/08 06:00
PHST- 2020/02/05 00:00 [received]
PHST- 2020/02/07 00:00 [accepted]
PHST- 2020/02/08 06:00 [pubmed]
PHST- 2021/07/22 06:00 [medline]
PHST- 2020/02/08 06:00 [entrez]
AID - ERC-20-0004.R1 [pii]
AID - 10.1530/ERC-20-0004 [doi]
PST - ppublish
SO  - Endocr Relat Cancer. 2020 Apr;27(4):231-244. doi: 10.1530/ERC-20-0004.