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Regulation of FGF8 expression by the androgen receptor in human prostate cancer

Oncogene volume 21, pages 5069–5080 (2002)Cite this article

Abstract

Fibroblast growth factor 8 (FGF8) has been shown to play a key role in prostate carcinogenesis. It was initially cloned as an androgen induced protein in mouse mammary cancer SC3 cells. In this study, we examined if FGF8 was also regulated by the androgen receptor in human prostate cancer. FGF8b protein expression in resected clinical prostate cancer correlated closely with expression of the androgen receptor (AR). In the androgen sensitive CWR22 prostate xenograft, we observed up-regulation of FGF8b immunoreactivity in testosterone supplemented mice while castration markedly reduced its signal. Furthermore, FGF8b protein expression in AR positive LNCaP cells was similarly enhanced by androgens. The proximal promoter of the human FGF8 gene was cloned into a luciferase reporter construct (FGF8.luc). FGF8.luc activity in AR positive LNCaP and SC3 cells was increased 2.5-fold by androgens. In AR negative DU145 cells, maximal induction of FGF8.luc required both co-transfection of the AR and the presence of androgens. The anti-androgen bicalutamide completely abolished AR mediated FGF8.luc induction. Deletion constructs from FGF8.luc have further defined an active promoter region and an androgen responsive region. Nucleotide analysis of this androgen responsive region has revealed putative androgen response elements. Finally, using ChIP assays we confirmed in vivo interaction between the AR and the androgen responsive region of the FGF8 promoter. Taken together these data provide first evidence that expression of the mitogen FGF8 in prostate cancer is, at least in part, regulated by the androgen receptor at the transcriptional level.

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Article 04 February 2021

Richard J. Rebello, Christoph Oing, … Robert G. Bristow

Abbreviations

AR:

androgen receptor

ARE:

androgen response element

FGF8:

fibroblast growth factor 8

ChIP:

chromatin immunoprecipitation

CWR22:

Case Western Reserve Prostate Xenograft strain 22

MMTV:

mouse mammary tumour virus

PCR:

polymerase chain reaction

PSA:

prostate specific antigen

SHR:

steroid hormone receptor

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Acknowledgements

This project was funded by the Cancer Research Campaign of the UK, grant no SP2503/0101. We thank Dr Clive Dickson (Imperial Cancer Research Fund, London, UK) for the human FGF8 genomic clone, Professor TG Pretlow (Case Western Reserve University, Cleveland, Ohio, USA) for the CWR22 cells, Professor DR Newell (Cancer Research Unit, University of Newcastle-upon-Tyne) for assistance with the animal studies. We thank Susan Cook and Louise McCarthy for expert technical assistance.

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  1. Prostate Research Group, School of Surgical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK

    Vincent J Gnanapragasam, Craig N Robson, David E Neal & Hing Y Leung

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  1. Vincent J Gnanapragasam
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  2. Craig N Robson
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Correspondence to Hing Y Leung.

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Gnanapragasam, V., Robson, C., Neal, D. et al. Regulation of FGF8 expression by the androgen receptor in human prostate cancer. Oncogene 21, 5069–5080 (2002). https://doi.org/10.1038/sj.onc.1205663

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