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  • Original Paper
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Ligand-dependent inhibition of β-catenin/TCF signaling by androgen receptor

Oncogene volume 21, pages 8453–8469 (2002)Cite this article

Abstract

β-catenin signaling may contribute to prostate cancer (CaP) progression. Although β-catenin is known to upregulate T cell factor (TCF) target gene expression in CaP cells, recent evidence demonstrates its capacity to enhance ligand-dependent androgen receptor (AR) function. Thus, we wished to further understand the interaction between these two pathways. We find in both CaP cells (CWR22-Rv1, LAPC-4, DU145) and non-CaP cells (HEK-293, TSU, SW480, HCT-116) that β-catenin/TCF-related transcription (CRT), as measured by activation of a synthetic promoter and that of cyclin D1, is inhibited by androgen treatment. This inhibition is AR-dependent, as it only occurs in cells expressing AR endogenously or transiently, and is abrogated by AR antagonists. Additional analyses convey that the ligand-dependent nature of CRT suppression depends on transactivation-competent AR in the nucleus, but not on indirect effects stemming from AR target gene expression. Given the recent work identifying an AR/β-catenin interaction, and from our finding that liganded AR does not prompt gross changes in the constitutive nuclear localization of TCF4 or mutant β-catenin, we hypothesized that transcription factor (i.e. AR and TCF) competition for β-catenin recruitment may explain, in part, androgen-induced suppression of CRT. To address this idea, we expressed an AR mutant lacking its DNA-binding domain (DBD). This receptor could not orchestrate ligand-dependent CRT repression, thereby providing support for those recent data implicating the AR DBD/LBD as necessary for β-catenin interaction. Further supporting this hypothesis, TCF/LEF over-expression counteracts androgen-induced suppression of CRT, and requires β-catenin binding activity to do so. Interestingly, TCF4 over-expression potently antagonizes AR function; however, this inhibition may occur independently of β-catenin/TCF4 interaction. These results from TCF4 over-expression analyses, taken together, provide further evidence that AR-mediated suppression of CRT is a consequence of limiting amounts of β-catenin, and not AR target gene expression. Our analyses point to a reciprocal balance between AR and CRT function that may shape critical processes during normal prostate development and tumor progression.

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Acknowledgements

This work was supported by PHS grand CA58236. We are grateful towards Dr Ken Kinzler (JHU), Dr John Isaacs (JHU), and Dr Ron Rodriguez (JHU) for generously supplying reagents used in this study.

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  1. Brady Urological Institute Research Laboratories, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, MD, USA

    Dennis R Chesire & William B Isaacs

  2. Johns Hopkins Oncology Center, The Johns Hopkins Medical Institutions, Baltimore, 21287, Maryland, MD, USA

    William B Isaacs

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Chesire, D., Isaacs, W. Ligand-dependent inhibition of β-catenin/TCF signaling by androgen receptor. Oncogene 21, 8453–8469 (2002). https://doi.org/10.1038/sj.onc.1206049

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