Advertisement

Glucocorticoid receptor in cervical cancer: an immunhistochemical analysis

  • Bernd Peter Kost
  • Susanne Beyer
  • Lennard Schröder
  • Junyan Zhou
  • Doris Mayr
  • Christina Kuhn
  • Sandra Schulze
  • Simone Hofmann
  • Sven Mahner
  • Udo Jeschke
  • Helene Heidegger
Gynecologic Oncology
  • 20 Downloads

Abstract

Purpose

Cervical cancer is one of the most frequent cancers in women worldwide. In most of all cases, a persistent HPV infection is the leading cause. HPV-specific sequences are able to bind glucocorticoid receptor (GR). Dexamethasone can increase the activity of early promoters in HPV16 and HPV18 interfering in transcription control of viral oncogenes. The aim of our study was to evaluate glucocorticoid receptor as transcriptional factor in its active form in the nucleus of in cervical cancer cells and to correlate the results with clinical patient specific parameters.

Methods

A total of 250 paraffin-embedded cervical cancer samples obtained from patients having undergone surgery for cervical cancer were used for the study. The expression of GR was immunhistochemical examined and evaluated by a semi-quantitative scoring. SPSS software was used for the statistical evaluation of staining results and survival analysis of patients with cervical cancer.

Results

GR is frequently expressed in cervical carcinoma tissue in favor of squamous cell carcinoma (SCC). An enhanced expression is correlated with rather small clinical stages. The expression of the GR is correlated with better overall survival and progression-free survival.

Conclusions

The glucocorticoid receptor is frequently expressed in cervical carcinoma tissue in favor of squamous cell carcinoma. An enhanced expression is correlated with rather small clinical stages. The expression of the analyzed receptor is correlated with better overall survival. Further studies are needed to determine useful treatment targets for glucocorticoid receptor manipulation.

Keywords

Cervical cancer Glucocorticoid receptor Survival 

Notes

Author contributions

BPK: project development, data collection. SB: experiments, manuscript writing. LS: data collection, manuscript editing. JZ: data analyses. DM: supervision, data analyses. CK: experiments, methodology. SS: experiments, methodology. SH: experiments, methodology. SM: data analyses, supervision, funding. UJ: supervision. HH: manuscript edition, data analyses

Funding

The study was supported by the “Heuer Stiftung” for Bernd P. Kost. The authors would like to thank Prof. Dr. med. Jutta Engel, M.P.H. and Max Wiedemann (The Munich Cancer Registry of the Tumorzentrum München [TZM—Munich Tumor Center]) for the follow-up data.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

The study was approved by the ethics committee of the Ludwig-Maximilians University Munich (reference number 259-16). Patient data were anonymized.

References

  1. 1.
    Munoz N, Bosch FX, Castellsague X, Diaz M, de Sanjose S, Hammouda D, Shah KV, Meijer CJ (2004) Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 111:278–285CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Serrano-Olvera A, Cetina L, Coronel J, Duenas-Gonzalez A (2014) Follow-up consultations for cervical cancer patients in a mexican cancer center. Comparison with NCCN guidelines. Asian Pac J Cancer Prev 15:8749–8752CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Horn LC, Beckmann MW, Follmann M, Koch MC, Mallmann P, Marnitz S, Schmidt D, German Cancer S (2015) s3 guidelines on diagnostics and treatment of cervical cancer: demands on pathology. Pathologe 36:585–593CrossRefPubMedCentralGoogle Scholar
  4. 4.
    Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S (2007) Human papillomavirus and cervical cancer. Lancet 370:890–907CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Wittekindt C, Wagner S, Mayer CS, Klussmann JP (2012) basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer. Laryngorhinootologie 91(Suppl 1):S1–S26PubMedPubMedCentralGoogle Scholar
  6. 6.
    Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ, International Agency for Research on Cancer Multicenter Cervical Cancer Study G (2003) Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348:518–527CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Liu J, Cheng Y, He M, Yao S (2014) Vascular endothelial growth factor c enhances cervical cancer cell invasiveness via upregulation of galectin-3 protein. Gynecol Endocrinol 30:461–465CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Meng CF, Su B, Li W (2011) DNA demethylation is superior to histone acetylation for reactivating cancer-associated genes in ovarian cancer cells. Mol Med Rep 4:1273–1278PubMedPubMedCentralGoogle Scholar
  9. 9.
    Gupta S, Takhar PP, Degenkolbe R, Koh CH, Zimmermann H, Yang CM, Guan Sim K, Hsu SI, Bernard HU (2003) The human papillomavirus type 11 and 16 e6 proteins modulate the cell-cycle regulator and transcription cofactor trip-br1. Virology 317:155–164CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The hpv-16 e6 and e6-ap complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495–505CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Pittayakhajonwut D, Angeletti PC (2010) Viral trans-factor independent replication of human papillomavirus genomes. Virol J 7:123CrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bromberg-White JL, Meyers C (2002) The upstream regulatory region of human papillomavirus type 31 is insensitive to glucocorticoid induction. J Virol 76:9702–9715CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Chan WK, Klock G, Bernard HU (1989) Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia. J Virol 63:3261–3269PubMedPubMedCentralGoogle Scholar
  14. 14.
    Webster K, Taylor A, Gaston K (2001) Oestrogen and progesterone increase the levels of apoptosis induced by the human papillomavirus type 16 e2 and e7 proteins. J Gen Virol 82:201–213CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Kwasniewska A, Postawski K, Gozdzicka-Jozefiak A, Kwasniewski W, Grywalska E, Zdunek M, Korobowicz E (2011) Estrogen and progesterone receptor expression in HPV-positive and HPV-negative cervical carcinomas. Oncol Rep 26:153–160PubMedPubMedCentralGoogle Scholar
  16. 16.
    Fonseca-Moutinho JA, Cruz E, Carvalho L, Prazeres HJ, de Lacerda MM, da Silva DP, Mota F, de Oliveira CF (2004) Estrogen receptor, progesterone receptor, and BCL-2 are markers with prognostic significance in cin iii. Int J Gynecol Cancer 14:911–920CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Chen YH, Huang LH, Chen TM (1996) Differential effects of progestins and estrogens on long control regions of human papillomavirus types 16 and 18. Biochem Biophys Res Commun 224:651–659CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Schlossmacher G, Stevens A, White A (2011) Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. J Endocrinol 211:17–25CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Block TS, Murphy TI, Munster PN, Nguyen DP, Lynch FJ (2017) Glucocorticoid receptor expression in 20 solid tumor types using immunohistochemistry assay. Cancer Manag Res 9:65–72.  https://doi.org/10.2147/CMAR.S124475 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Stiasny A, Freier CP, Kuhn C, Schulze S, Mayr D, Alexiou C, Janko C, Wiest I, Dannecker C, Jeschke U et al (2017) The involvement of e6, p53, p16, mdm2 and gal-3 in the clinical outcome of patients with cervical cancer. Oncol Lett 14:4467–4476CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Friese K, Kost B, Vattai A, Marme F, Kuhn C, Mahner S, Dannecker C, Jeschke U, Heublein S (2018) The g protein-coupled estrogen receptor (gper/gpr30) may serve as a prognostic marker in early-stage cervical cancer. J Cancer Res Clin Oncol 144:13–19CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Vattai A, Cavailles V, Sixou S, Beyer S, Kuhn C, Peryanova M, Heidegger H, Hermelink K, Mayr D, Mahner S et al (2017) Investigation of rip140 and lcor as independent markers for poor prognosis in cervical cancer. Oncotarget 8:105356–105371CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Beyer S, Zhu J, Mayr D, Kuhn C, Schulze S, Hofmann S, Dannecker C, Jeschke U, Kost BP (2017) Histone h3 acetyl k9 and histone h3 tri methyl k4 as prognostic markers for patients with cervical cancer. Int J Mol Sci.  https://doi.org/10.3390/ijms18030477 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Marth C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colombo N, Committee E G (2017) Cervical cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 28:iv72–iv83CrossRefGoogle Scholar
  25. 25.
    Reich O, Regauer S, Marth C, Schmidt D, Horn LC, Dannecker C, Menton M, Beckmann MW (2015) Precancerous lesions of the cervix, vulva and vagina according to the 2014 who classification of tumors of the female genital tract. Geburtshilfe Frauenheilkd 75:1018–1020CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Freier CP, Stiasny A, Kuhn C, Mayr D, Alexiou C, Janko C, Wiest I, Jeschke U, Kost B (2016) Immunohistochemical evaluation of the role of p53 mutation in cervical cancer: Ser-20 p53-mutant correlates with better prognosis. Anticancer Res 36:3131–3137PubMedPubMedCentralGoogle Scholar
  27. 27.
    Stiasny A, Kuhn C, Mayr D, Alexiou C, Janko C, Wiest I, Jeschke U, Kost B (2016) Immunohistochemical evaluation of e6/e7 hpv oncoproteins staining in cervical cancer. Anticancer Res 36:3195–3198PubMedPubMedCentralGoogle Scholar
  28. 28.
    Kolben TM, Kraft F, Kolben T, Goess C, Semmlinger A, Dannecker C, Schmoeckel E, Mayr D, Sommer NN, Mahner S et al (2017) Expression of sialyl lewis a, sialyl lewis x, lewis y, gal-3, gal-7, stmn1 and p16 in cervical dysplasia. Future Oncol 13:145–157CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Vanderbilt JN, Miesfeld R, Maler BA, Yamamoto KR (1987) Intracellular receptor concentration limits glucocorticoid-dependent enhancer activity. Mol Endocrinol 1:68–74CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Gehring U, Mugele K, Ulrich J (1984) Cellular receptor levels and glucocorticoid responsiveness of lymphoma cells. Mol Cell Endocrinol 36:107–113CrossRefPubMedCentralGoogle Scholar
  31. 31.
    Herr I, Buchler MW, Mattern J (2009) Glucocorticoid-mediated apoptosis resistance of solid tumors. Results Probl Cell Differ 49:191–218CrossRefPubMedCentralGoogle Scholar
  32. 32.
    Arora Vivek K, Schenkein Emily, Murali Rajmohan et al (2013) Glucocorticoid receptor confers resistance to anti-androgens by bypassing androgen receptor blockade. Cell 155(6):1309–1322CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Hunt H, Donaldson K, Strem M, Zann V, Leung P, Sweet S, Connor A, Combs D, Belanoff J (2017) Assessment of safety, tolerability, pharmacokinetics, and pharmacological effect of orally administered cort125134: An adaptive, double-blind, randomized, placebo-controlled phase 1 clinical study. Clin Pharmacol Drug Dev 7(4):408–421.  https://doi.org/10.1002/cpdd.389 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hunt HJ, Belanoff JK, Walters I, Gourdet B, Thomas J, Barton N, Unitt J, Phillips T, Swift D, Eaton E (2017) Identification of the clinical candidate (r)-(1-(4-fluorophenyl)-6-((1-methyl-1 h-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexah ydro-1 h-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methano ne (cort125134): a selective glucocorticoid receptor (gr) antagonist. J Med Chem 60:3405–3421CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Bernd Peter Kost
    • 1
  • Susanne Beyer
    • 1
  • Lennard Schröder
    • 1
  • Junyan Zhou
    • 1
  • Doris Mayr
    • 2
  • Christina Kuhn
    • 1
  • Sandra Schulze
    • 1
  • Simone Hofmann
    • 1
  • Sven Mahner
    • 1
  • Udo Jeschke
    • 1
  • Helene Heidegger
    • 1
  1. 1.Department of Obstetrics and GynecologyLMU Munich, University HospitalMunichGermany
  2. 2.Klinikum Der Universität München, Pathologisches InstitutMunichGermany

Personalised recommendations