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Molecular Medicine

, Volume 18, Issue 11, pp 1456–1465 | Cite as

Glucocorticoid Receptor and Molecular Chaperones in the Pathogenesis of Adrenal Incidentalomas: Potential Role of Reduced Sensitivity to Glucocorticoids

  • Svetozar S. Damjanovic
  • Jadranka A. Antic
  • Bojana B. Ilic
  • Bojana Beleslin Cokic
  • Miomira Ivovic
  • Sanja I. Ognjanovic
  • Tatjana V. Isailovic
  • Bojana M. Popovic
  • Ivana B. Bozic
  • Svetislav Tatic
  • Gordana Matic
  • Vera N. Todorovic
  • Ivan Paunovic
Research Article

Abstract

Glucocorticoid (GC) sensitivity depends on glucocorticoid receptor (GR) and heat shock proteins (Hsps). We investigated whether common GR genes (ER22/23EK N363S, Bcl I, and 9β) and adrenocorticotropin receptor promoter polymorphisms influence susceptibility for unilateral adrenal incidentaloma (AI), plus GR and Hsp expression in tumorous (n = 19), peritumorous (n = 13) and normal adrenocortical (n = 11) tissues. Patients (n = 112), population-matched controls (n = 100) and tumor tissues (n = 32) were genotyped for these polymorphisms. Postdexamethasone serum cortisol was higher in patients (p < 0.001). GR gene variants, larger allele of Bcl I (odds ratio (OR) 2.9; 95% confidence interval (CI) 1.7–5.1; p < 0.001] and minor allele of 9β (OR 3.0; 95% CI 1.6–5.7; p < 0.001) were independent predictors of AI. In patients, the first allele is linked with larger tumors (p = 0.002) and the latter with higher postdexamethasone cortisol levels (p = 0.025). Both allele carriers had lesser waist circumference (p = 0.02), similar adrenocorticotropin and higher basal (p = 0.024) and postdexamethasone cortisol concentrations (p < 0.001). Tumorous and constitutional genotypes were similar. GR-D is the major receptor isoform in normal adrenal cortex by Western blotting. Loss of other receptor iso-forms, decrease in immunostaining for GR (p < 0.0001), underexpression of chaperones (p ≤ 0.01) and the presence of inducible Hsp70 were found in adenomas. In conclusion, GR gene variants, C allele of Bcl I and minor allele of 9β, are associated with Als. Their concurrent presence in patients reduces GC sensitivity. Normal adrenal cortex preferentially expresses GR-D. In adenomas, the lack of other GR isoforms and underexpression of heat shock proteins perhaps permanently impair GC signaling, which could promote dysregulated cortisol production and tumor growth. The innate GC sensitivity probably modifies these effects.

Notes

Acknowledgments

The authors are indebted to Neda Drndarevic and Zoran Sinadinovic for technical assistance and hormonal measurements. This study was supported by the Ministry of Science and Technological Development of Serbia (grant III41009).

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Authors and Affiliations

  • Svetozar S. Damjanovic
    • 1
  • Jadranka A. Antic
    • 1
  • Bojana B. Ilic
    • 1
  • Bojana Beleslin Cokic
    • 1
  • Miomira Ivovic
    • 1
  • Sanja I. Ognjanovic
    • 1
  • Tatjana V. Isailovic
    • 1
  • Bojana M. Popovic
    • 1
  • Ivana B. Bozic
    • 1
  • Svetislav Tatic
    • 2
  • Gordana Matic
    • 3
  • Vera N. Todorovic
    • 4
  • Ivan Paunovic
    • 5
  1. 1.Centre for Endocrine Oncology and Hereditary Cancer Syndromes, Institute for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Centre of SerbiaUniversity of BelgradeBelgradeSerbia
  2. 2.Institute for PathologyUniversity of BelgradeBelgradeSerbia
  3. 3.Department of Biochemistry, Institute for Biological Research “Sinisa Stankovic”University of BelgradeBelgradeSerbia
  4. 4.Faculty of Stomatology in PancevoUniversity of Business AcademyNovi SadSerbia
  5. 5.Centre for Endocrine Surgery, Institute for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Centre of SerbiaUniversity of BelgradeBelgradeSerbia

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