title: 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.
authors.affiliation: Centre for Endocrine Oncology and Hereditary Cancer Syndromes, Institute for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Centre of Serbia, University of Belgrade, Belgrade, Serbia. sova@net.co.rs
authors.forename: Svetozar S
authors.initials: SS
authors.lastname: Damjanovic
authors.forename: Jadranka A
authors.initials: JA
authors.lastname: Antic
authors.forename: Bojana B
authors.initials: BB
authors.lastname: Ilic
authors.forename: Bojana Beleslin
authors.initials: BB
authors.lastname: Cokic
authors.forename: Miomira
authors.initials: M
authors.lastname: Ivovic
authors.forename: Sanja I
authors.initials: SI
authors.lastname: Ognjanovic
authors.forename: Tatjana V
authors.initials: TV
authors.lastname: Isailovic
authors.forename: Bojana M
authors.initials: BM
authors.lastname: Popovic
authors.forename: Ivana B
authors.initials: IB
authors.lastname: Bozic
authors.forename: Svetislav
authors.initials: S
authors.lastname: Tatic
authors.forename: Gordana
authors.initials: G
authors.lastname: Matic
authors.forename: Vera N
authors.initials: VN
authors.lastname: Todorovic
authors.forename: Ivan
authors.initials: I
authors.lastname: Paunovic
mesh_terms: D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D016022:Case-Control Studies; D002457:Cell Extracts; D005260:Female; D020022:Genetic Predisposition to Disease; D005938:Glucocorticoids / Q000494:pharmacology*; D006239:Haplotypes / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018043:Receptors, Corticotropin / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012307:Risk Factors; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D005938:Glucocorticoids; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D018043:Receptors, Corticotropin; D011965:Receptors, Glucocorticoid