The Aryl Hydrocarbon Receptor (AHR) May Act As a Tumour Suppressor in Pituitary Adenomas
Presentation Number: LBF-083
Date of Presentation: March 6th, 2015
Robert Formosa*1, Joseph Borg2 and Josanne Vassallo1
1University of Malta, Msida, Malta, 2University of Malta, Mater Dei Hospital, Msida, Malta
Research to elucidate molecular mechanisms driving pituitary tumour formation and progression is essential given the dearth of data regarding pathways involved. In order to identify novel mechanisms driving pituitary adenomas (PA) growth, RNA profiling microarray analysis was carried out on locally resected PAs (5 non-functioning, 2 growth hormone secreting and one prolactin-secreting PA). Ingenuity pathway analysis identified the aryl hydrocarbon receptor signaling pathway as a key canonical pathway deregulated in all PA types. A general down – regulation of AHR downstream targets and co-regulators was observed in all tumours as compared to pooled control RNA and confirmed by quantitative PCR in a total of 31 tumours. Proliferation analysis using MTT assays and a number of functional analyses were then used to validate the role of the AHR in PA using the GH3 sommatotroph/lactotroph cell line. GH3 cells were transfected with AHR expression vector and activated using benzo α-pyrene (BαP) ligand. AHR over-expression alone reduced GH3 cell proliferation significantly in the presence and absence of exogenous ligand, indicating a possible tumour suppressive role. However, over-expressed AHR induced a xenobiotic response only in the presence of BαP, indicating that an exogenous agent activating the canonical xenobiotic signaling pathway may not be required for AHR to carry out its anti-proliferative behavior in GH3 cells. Cell cycle analysis and quantitative PCR of cell cycle regulator genes revealed that both unstimulated and BαP-stimulated AHR alters specific non-xenobiotic pathways shifting the percentage of cells in G0/G1 phase and thereby slowing the proliferation rate of GH3 cells. The evidence provided corroborates a role for the AHR as a putative suppressor of pituitary tumour formation, possibly through its role as an indirect cell cycle co-regulator.
Nothing to Disclose: RF, JB, JV