Key Points
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Several molecular characterization studies have identified members of the forkhead box (FOX) superfamily of transcription factors as being differentially expressed in molecular subtypes of bladder cancer
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As several of these FOX proteins are also involved in urothelial development and/or differentiation, these findings suggest that they might have a potential direct function in bladder cancer pathophysiology
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Differential expression of several FOX family members, including FOXA1, is associated with clinical outcomes in patients with bladder cancer
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Basic science studies have confirmed roles for some specific FOX proteins in bladder cancer
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Further investigation is required to determine the extent and mechanism by which these transcription factors might directly contribute to tumour initiation, progression and responses to standard and emerging therapies
Abstract
Genomic and transcriptional studies have identified discrete molecular subtypes of bladder cancer. These observations could be the starting point to identify new treatments. Several members of the forkhead box (FOX) superfamily of transcription factors have been found to be differentially expressed in the different bladder cancer subtypes. In addition, the FOXA protein family are key regulators of embryonic bladder development and patterning. Both experimental and clinical data support a role for FOXA1 and FOXA2 in urothelial carcinoma. FOXA1 is expressed in embryonic and adult urothelium and its expression is altered in urothelial carcinomas and across disparate molecular bladder cancer subtypes. FOXA2 is normally absent from the adult urothelium, but developmental studies identified FOXA2 as a marker of a transient urothelial progenitor cell population during bladder development. Studies also implicate FOXA2 in bladder cancer and several other FOX proteins might be involved in development and/or progression of this disease; for example, FOXA1 and FOXO3A have been associated with clinical patient outcomes. Future studies should investigate to what extent and by which mechanisms FOX proteins might be directly involved in bladder cancer pathogenesis and treatment responses.
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Acknowledgements
We wish to gratefully acknowledge the thoughtful discussions with Dr T. Schell, Dr E. Plimack and Dr S. Holder regarding FOXP3 and the use of immune checkpoint inhibitors for the treatment of bladder cancer. In addition, the authors would like to thank L. Shuman for critically reading and discussing the manuscript. D.J.D. is supported by a Young Investigator Award from the Bladder Cancer Advocacy Network and a National Cancer Institute grant (R00CA172122). J.D.R. is supported by the Ken and Bonney Shockey Fund for Urologic Research.
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P.E.C. and D.J.D. have a patent pending for the use of FOXA1 as a prognostic marker in bladder cancer. H.Y., V.O.A., J.I.W., Z.Z., J.D.R., X.-R.W. and C.M. declare no competing interests.
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Yamashita, H., Amponsa, V., Warrick, J. et al. On a FOX hunt: functions of FOX transcriptional regulators in bladder cancer. Nat Rev Urol 14, 98–106 (2017). https://doi.org/10.1038/nrurol.2016.239
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DOI: https://doi.org/10.1038/nrurol.2016.239
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