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Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype

Oncogene volume 33, pages 5666–5674 (2014)Cite this article

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Abstract

Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second-line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR-targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by overexpressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (hazard ratio (HR) 5.0, 95% confidence interval (CI) 1.2–21.1, P=0.028), positive surgical margins and higher stage disease at diagnosis. The gene expression program that results from FOXA1 overexpression is enriched for PTEN, Wnt and other pathways typically represented in CRPC gene signatures. Together, these results suggest that in an androgen-depleted state, elevated levels of FOXA1 enhance AR binding at genomic regions not normally occupied by AR, which in turn facilitates prostate cancer cell growth.

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Abbreviations

ADT:

androgen deprivation therapy

AR:

androgen receptor

ARBS:

androgen receptor binding site

ChIP:

chromatin immunoprecipitation

CRPC:

castrate-resistant prostate cancer

DEG:

differentially regulated genes

DHT:

5α-dihydrotestosterone

RIME:

rapid immunoprecipitation of endogenous proteins.

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Acknowledgements

We would like to thank the members of the genomic, proteomic and histopathology core facilities at Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. We are grateful to study volunteers for their participation and staff at the Welcome Trust Clinical Research Facility, Addenbrooke’s Clinical Research Centre, Cambridge. WDT is supported by grants from the National Health and Medical Research Council of Australia (ID 627185), Cancer Australia (ID 627229) and the Prostate Cancer Foundation of Australia. TEH holds a Postdoctoral Fellowship Award from the US Department of Defense Breast Cancer Research Program (BCRP; #W81XWH-11-1-0592). JSC is supported by an ERC starting grant and an EMBO Young Investigator Award.

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Authors and Affiliations

  1. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    J L L Robinson, S L Vowler, T Carroll, A D Lamb, D E Neal & J S Carroll

  2. Department of Oncology, University of Cambridge, Cambridge, UK

    J L L Robinson, S L Vowler, T Carroll, A D Lamb, D E Neal & J S Carroll

  3. Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    T E Hickey, D E Neal & W D Tilley

  4. Department of Histopathology, Cambridge University Hospitals NHS Foundations Trust, Cambridge, UK

    A Y Warren

  5. Department of Urology, Cambridge University Hospitals NHS Foundations Trust, Cambridge, UK

    A D Lamb & N Papoutsoglou

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Robinson, J., Hickey, T., Warren, A. et al. Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype. Oncogene 33, 5666–5674 (2014). https://doi.org/10.1038/onc.2013.508

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