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

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 isoforms, 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 AIs. 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.

Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study

“…Nevertheless, despite the number of Muta-GR patients, a direct relationship between bilateral adrenal incidentaloma and minor allelic frequencies of some common GR polymorphisms (rs6189, rs6190, rs10482622, rs6195, rs41423247, rs6188 and rs6196) has not been established. This contrasts with other studies that have suggested a role of these polymorphisms in unilateral adrenal incidentaloma (47,48). Altogether, except BclI, no association was found between the presence of such polymorphisms and bilateral adrenal hyperplasia in our series.…”

Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin‐releasing factor receptor 1 cell group

“…The glucocorticoid receptor (GR) polyclonal antibody (RRID: AB_2155786) was generated against a peptide at the N‐terminus of GRα of mouse origin (5–24) (manufacturer's information). Western blotting shows a specifically labeled band at 110 kDa in adrenal tissue (Damjanovic et al, ). Peptide preabsorption studies have been used to confirm specificity of this antibody (Damjanovic et al, ).…”

“…Western blotting shows a specifically labeled band at 110 kDa in adrenal tissue (Damjanovic et al, ). Peptide preabsorption studies have been used to confirm specificity of this antibody (Damjanovic et al, ). Brain distributions of GR in our labeled tissue also match those reported in Allen Institute ISH data, with highest levels found in the paraventricular hypothalamus, central amygdala, and hippocampus.…”

“…Western blotting shows a specifically labeled band at 110 kDa in adrenal tissue (Damjanovic et al, 2013). Peptide preabsorption studies have been used to confirm specificity of this antibody (Damjanovic et al, 2013).…”

The Occurrence of Subclinical Hypercortisolism and Osteoporosis in Patients with Incidentally Discovered Unilateral and Bilateral Adrenal Tumors

“…This could be due to the different duration of hypercortisolism and interindividual variations in glucocorticoid sensitivity, which depends on the polymorphism of both glucocorticoid receptor (GR) and 11-hydroxysteroid-dehydrogenase type 1 genes (35, 36). In our previous study we have shown that GR gene variants, larger allele of BclI and minor allele of 9 b, were associated with predisposition to the development of UAI and reduced sensitivity to glucocorticoids (37). Increased prevalence of vertebral fractures was found in patients carriers of heterozygous N363S and homozygous BclI polymorphism of GR regardless of the degree of dysfunctional cortisol secretion (38).…”