Digestive Diseases and Sciences

, Volume 61, Issue 2, pp 433–443 | Cite as

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

  • Eric Smith
  • Helen M. Palethorpe
  • Andrew R. Ruszkiewicz
  • Suzanne Edwards
  • Damien A. Leach
  • Tim J. Underwood
  • Eleanor F. Need
  • Paul A. Drew
Original Article

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.

Keywords

Adenocarcinoma of the esophagus Androgen receptors FK506-binding protein 5 Steroids Prognosis 

Supplementary material

10620_2015_3909_MOESM1_ESM.docx (79 kb)
Supplementary material 1 (DOCX 78 kb)
10620_2015_3909_MOESM2_ESM.docx (101 kb)
Supplementary material 2 (DOCX 101 kb)
10620_2015_3909_MOESM3_ESM.docx (95 kb)
Supplementary material 3 (DOCX 95 kb)

References

  1. 1.
    Lagergren J, Mattsson F. Diverging trends in recent population-based survival rates in oesophageal and gastric cancer. PLoS One. 2012;7:e41352.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Lord RV, Law MG, Ward RL, Giles GG, Thomas RJ, Thursfield V. Rising incidence of oesophageal adenocarcinoma in men in Australia. J Gastroenterol Hepatol. 1998;13:356–362.CrossRefPubMedGoogle Scholar
  3. 3.
    Dodaran MS, Silcocks PB, Logan RFA. Continuing rise in incidence of oesophageal adenocarcinoma in England and Wales. Gut. 2001;48:110.CrossRefGoogle Scholar
  4. 4.
    Rutegard M, Lagergren P, Nordenstedt H, Lagergren J. Oesophageal adenocarcinoma: the new epidemic in men? Maturitas. 2011;69:244–248.CrossRefPubMedGoogle Scholar
  5. 5.
    van Soest EM, Siersema PD, Dieleman JP, Sturkenboom MC, Kuipers EJ. Age and sex distribution of the incidence of Barrett’s esophagus found in a Dutch primary care population. Am J Gastroenterol. 2005;100:2599–2600.CrossRefPubMedGoogle Scholar
  6. 6.
    Derakhshan MH, Liptrot S, Paul J, Brown IL, Morrison D, McColl KE. Oesophageal and gastric intestinal-type adenocarcinomas show the same male predominance due to a 17 year delayed development in females. Gut. 2009;58:16–23.CrossRefPubMedGoogle Scholar
  7. 7.
    Akgun H, Lechago J, Younes M. Estrogen receptor-beta is expressed in Barrett’s metaplasia and associated adenocarcinoma of the esophagus. Anticancer Res. 2002;22:1459–1461.PubMedGoogle Scholar
  8. 8.
    Tiffin N, Suvarna SK, Trudgill NJ, Riley SA. Sex hormone receptor immunohistochemistry staining in Barrett’s oesophagus and adenocarcinoma. Histopathology. 2003;42:95–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Sukocheva OA, Wee C, Ansar A, Hussey DJ, Watson DI. Effect of estrogen on growth and apoptosis in esophageal adenocarcinoma cells. Dis Esophagus. 2013;26:628–635.CrossRefPubMedGoogle Scholar
  10. 10.
    Cook MB, Wood SN, Cash BD, et al. Association between circulating levels of sex steroid hormones and Barrett’s esophagus in men: a case-control analysis. Clin Gastroenterol Hepatol. 2015;13:673–682.CrossRefPubMedGoogle Scholar
  11. 11.
    Awan AK, Iftikhar SY, Morris TM, et al. Androgen receptors may act in a paracrine manner to regulate oesophageal adenocarcinoma growth. Eur J Surg Oncol. 2007;33:561–568.CrossRefPubMedGoogle Scholar
  12. 12.
    Tihan T, Harmon JW, Wan X, et al. Evidence of androgen receptor expression in squamous and adenocarcinoma of the esophagus. Anticancer Res. 2001;21:3107–3114.PubMedGoogle Scholar
  13. 13.
    Cooper SC, Croft S, Day R, Thomson CS, Trudgill NJ. Patients with prostate cancer are less likely to develop oesophageal adenocarcinoma: could androgens have a role in the aetiology of oesophageal adenocarcinoma? Cancer Causes Control. 2009;20:1363–1368.CrossRefPubMedGoogle Scholar
  14. 14.
    Jiang X, Tseng CC, Bernstein L, Wu AH. Family history of cancer and gastroesophageal disorders and risk of esophageal and gastric adenocarcinomas: a case-control study. BMC Cancer. 2014;14:60.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Magee JA, Chang LW, Stormo GD, Milbrandt J. Direct, androgen receptor-mediated regulation of the FKBP5 gene via a distal enhancer element. Endocrinology. 2006;147:590–598.CrossRefPubMedGoogle Scholar
  16. 16.
    Makkonen H, Kauhanen M, Paakinaho V, Jaaskelainen T, Palvimo JJ. Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res. 2009;37:4135–4148.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Nelson PS, Clegg N, Arnold H, et al. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci USA. 2002;99:11890–11895.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Kwack MH, Sung YK, Chung EJ, et al. Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes. J Invest Dermatol. 2008;128:262–269.CrossRefPubMedGoogle Scholar
  19. 19.
    Leach DA, Need EF, Trotta AP, Grubisha MJ, Defranco DB, Buchanan G. Hic-5 influences genomic and non-genomic actions of the androgen receptor in prostate myofibroblasts. Mol Cell Endocrinol. 2014;384:185–199.CrossRefPubMedGoogle Scholar
  20. 20.
    Leach DA, Need EF, Toivanen R, et al. Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome. Oncotarget. 2015;6:16135–16150.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Eisermann K, Broderick CJ, Bazarov A, Moazam MM, Fraizer GC. Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site. Mol Cancer. 2013;12:7.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Wang G, Jones SJ, Marra MA, Sadar MD. Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006;25:7311–7323.CrossRefPubMedGoogle Scholar
  23. 23.
    Mostaghel EA, Page ST, Lin DW, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67:5033–5041.CrossRefPubMedGoogle Scholar
  24. 24.
    Smith E, Ruszkiewicz AR, Jamieson GG, Drew PA. IGFBP7 is associated with poor prognosis in oesophageal adenocarcinoma and is regulated by promoter DNA methylation. Br J Cancer. 2014;110:775–782.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Barry SC, Harder B, Brzezinski M, Flint LY, Seppen J, Osborne WR. Lentivirus vectors encoding both central polypurine tract and posttranscriptional regulatory element provide enhanced transduction and transgene expression. Hum Gene Ther. 2001;12:1103–1108.CrossRefPubMedGoogle Scholar
  26. 26.
    Need EF, Scher HI, Peters AA, et al. A novel androgen receptor amino terminal region reveals two classes of amino/carboxyl interaction-deficient variants with divergent capacity to activate responsive sites in chromatin. Endocrinology. 2009;150:2674–2682.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Kim SM, Park YY, Park ES, et al. Prognostic biomarkers for esophageal adenocarcinoma identified by analysis of tumor transcriptome. PLoS One. 2010;5:e15074.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Munoz J, Wheler JJ, Kurzrock R. Androgen receptors beyond prostate cancer: an old marker as a new target. Oncotarget. 2015;6:592–603.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Chang C, Lee SO, Yeh S, Chang TM. Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogene. 2014;33:3225–3234.CrossRefPubMedGoogle Scholar
  30. 30.
    Staibano S, Mascolo M, Ilardi G, Siano M, De Rosa G. Immunohistochemical analysis of FKBP51 in human cancers. Curr Opin Pharmacol. 2011;11:338–347.CrossRefPubMedGoogle Scholar
  31. 31.
    Romano S, Staibano S, Greco A, et al. FK506 binding protein 51 positively regulates melanoma stemness and metastatic potential. Cell Death Dis. 2013;4:e578.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Jiang W, Cazacu S, Xiang C, et al. FK506 binding protein mediates glioma cell growth and sensitivity to rapamycin treatment by regulating NF-kappaB signaling pathway. Neoplasia. 2008;10:235–243.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Mukaide H, Adachi Y, Taketani S, et al. FKBP51 expressed by both normal epithelial cells and adenocarcinoma of colon suppresses proliferation of colorectal adenocarcinoma. Cancer Invest. 2008;26:385–390.CrossRefPubMedGoogle Scholar
  34. 34.
    Periyasamy S, Hinds T Jr, Shemshedini L, Shou W, Sanchez ER. FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene. 2010;29:1691–1701.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Romano S, D’Angelillo A, Staibano S, Ilardi G, Romano MF. FK506-binding protein 51 is a possible novel tumoral marker. Cell Death Dis. 2010;1:e55.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Amler LC, Agus DB, LeDuc C, et al. Dysregulated expression of androgen-responsive and nonresponsive genes in the androgen-independent prostate cancer xenograft model CWR22-R1. Cancer Res. 2000;60:6134–6141.PubMedGoogle Scholar
  37. 37.
    Velasco AM, Gillis KA, Li Y, et al. Identification and validation of novel androgen-regulated genes in prostate cancer. Endocrinology. 2004;145:3913–3924.CrossRefPubMedGoogle Scholar
  38. 38.
    Pei H, Li L, Fridley BL, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell. 2009;16:259–266.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev. 1996;76:69–125.PubMedGoogle Scholar
  40. 40.
    Peehl DM. Primary cell cultures as models of prostate cancer development. Endocr Relat Cancer. 2005;12:19–47.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Solid Cancer Regulation Group, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth HospitalThe University of AdelaideWoodville SouthAustralia
  2. 2.Gastroenterology Research LaboratorySA PathologyAdelaideAustralia
  3. 3.Data Management and Analysis Centre, Royal Adelaide HospitalThe University of AdelaideAdelaideAustralia
  4. 4.Cancer Biology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth HospitalThe University of AdelaideWoodville SouthAustralia
  5. 5.Cancer Sciences Unit, Somers Cancer Research Building, Southampton General HospitalUniversity of SouthamptonSouthamptonUK
  6. 6.Breast Biology and Cancer Unit, Discipline of Surgery, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth HospitalThe University of AdelaideWoodville SouthAustralia
  7. 7.School of Nursing and MidwiferyFlinders UniversityAdelaideAustralia

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