Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications.
Germline mutations of the aryl hydrocarbon receptor (AHR)-interacting protein (AIP) gene confer a predisposition to pituitary adenomas (PA), usually in the setting of familial isolated PA. To provide further insights into the possible role of AIP in pituitary tumour pathogenesis, the expression of AIP and AHR was determined by real-time RT-PCR and/or immunohistochemistry (IHC) in a large series of PA (n=103), including 17 with AIP mutations (AIP(mut)). Variable levels of AIP and AHR transcripts were detected in all PA, with a low AHR expression (P<0.0001 versus AIP). Cytoplasmic AIP and AHR were detected by IHC in 84.0 and 38.6% of PA respectively, and significantly correlated with each other (P=0.006). Nuclear AHR was detected in a minority of PA (19.7%). The highest AIP expression was observed in somatotrophinomas and non-secreting (NS) PA, and multivariate analysis in somatotrophinomas showed a significantly lower AIP immunostaining in invasive versus non-invasive cases (P=0.019). AIP expression was commonly low in other secreting PA. AIP immunostaining was abolished in a minority of AIP(mut) PA, with a frequent loss of cytoplasmic AHR and no evidence of nuclear AHR. In contrast, AIP overexpression in a subset of NS PA could be accompanied by nuclear AHR immunopositivity. We conclude that down-regulation of AIP and AHR may be involved in the aggressiveness of somatotrophinomas. Overall, IHC is a poorly sensitive tool for the screening of AIP mutations. Data obtained on AHR expression suggest that AHR signalling may be differentially affected according to PA phenotype.
Jaffrain-Rea
Marie-Lise
ML
Department of Experimental Medicine, University of L'Aquila, via Vetoio, Coppito 2, 67100 L'Aquila, Italy. jaffrain.ml@libero.it
Angelini
Mariolina
M
Gargano
Donatella
D
Tichomirowa
Maria A
MA
Daly
Adrian F
AF
Vanbellinghen
Jean-François
JF
D'Innocenzo
Emanuela
E
Barlier
Anne
A
Giangaspero
Felice
F
Esposito
Vincenzo
V
Ventura
Luca
L
Arcella
Antonietta
A
Theodoropoulou
Marily
M
Naves
Luciana A
LA
Fajardo
Carmen
C
Zacharieva
Sabina
S
Rohmer
Vincent
V
Brue
Thierry
T
Gulino
Alberto
A
Cantore
Giampaolo
G
Alesse
Edoardo
E
Beckers
Albert
A
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010902:Pituitary Gland / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015175:Prolactinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D018336:Receptors, Aryl Hydrocarbon; C103265:aryl hydrocarbon receptor-interacting protein