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Androgen Receptor and Androgen-Responsive Gene FKBP5 Are Independent Prognostic Indicators for Esophageal Adenocarcinoma

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Abstract

Background

Esophageal adenocarcinoma is a male-dominant disease, but the role of androgens is unclear.

Aims

To examine the expression and clinical correlates of the androgen receptor (AR) and the androgen-responsive gene FK506-binding protein 5 (FKBP5) in esophageal adenocarcinoma.

Methods

Expression of AR and FKBP5 was determined by immunohistochemistry. The effect of the AR ligand 5α-dihydrotestosterone (DHT) on the expression of a panel of androgen-responsive genes was measured in AR-positive and AR-negative esophageal adenocarcinoma cell lines. Correlations in expression between androgen-responsive genes were analyzed in an independent cohort of esophageal adenocarcinoma tissues.

Results

There was AR staining in 75 of 77 cases (97 %), and FKBP5 staining in 49 (64 %), all of which had nuclear AR. Nuclear AR with FKBP5 expression was associated with decreased median survival (451 vs. 2800 days) and was an independent prognostic indicator (HR 2.894, 95 % CI 1.396–6.002, p = 0.0043) in multivariable Cox proportional hazards models. DHT induced a significant increase in expression of the androgen-responsive genes FKBP5, HMOX1, FBXO32, VEGFA, WNT5A, and KLK3 only in AR-positive cells in vitro. Significant correlations in expression were observed between these androgen-responsive genes in an independent cohort of esophageal adenocarcinoma tissues.

Conclusion

Nuclear AR and expression of FKBP5 is associated with decreased survival in esophageal adenocarcinoma.

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Acknowledgments

The authors would like to thank Mr. Bill Panagopoulos for technical assistance and provision of PCR primers.

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Author notes

    Authors and Affiliations

    1. Solid Cancer Regulation Group, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, The University of Adelaide, 28 Woodville Rd, Woodville South, SA, 5011, Australia

      Eric Smith, Helen M. Palethorpe & Paul A. Drew

    2. Gastroenterology Research Laboratory, SA Pathology, Frome Road, Adelaide, SA, 5000, Australia

      Andrew R. Ruszkiewicz

    3. Data Management and Analysis Centre, Royal Adelaide Hospital, The University of Adelaide, North Terrace, Adelaide, SA, 5005, Australia

      Suzanne Edwards

    4. Cancer Biology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, The University of Adelaide, 28 Woodville Rd, Woodville South, SA, 5011, Australia

      Damien A. Leach

    5. Cancer Sciences Unit, Somers Cancer Research Building, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK

      Tim J. Underwood

    6. Breast Biology and Cancer Unit, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, The University of Adelaide, 28 Woodville Rd, Woodville South, SA, 5011, Australia

      Eleanor F. Need

    7. School of Nursing and Midwifery, Flinders University, PO Box 2100, Adelaide, SA, 5001, Australia

      Paul A. Drew

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    1. Eric Smith
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    Correspondence to Eric Smith.

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    Eric Smith and Helen M. Palethorpe have contributed equally to this work.

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    Smith, E., Palethorpe, H.M., Ruszkiewicz, A.R. et al. Androgen Receptor and Androgen-Responsive Gene FKBP5 Are Independent Prognostic Indicators for Esophageal Adenocarcinoma. Dig Dis Sci 61, 433–443 (2016). https://doi.org/10.1007/s10620-015-3909-0

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    • DOI: https://doi.org/10.1007/s10620-015-3909-0

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