Endocrine Abstracts

Numerous growth factors, oncogenes, tumour suppressor genes and hormonal influences have been implicated in pituitary tumorigenesis. We have demonstrated that the PI3K-Akt pathway is upregulated in pituitary tumours and since Akt is a major downstream signalling molecule of growth factor-liganded tyrosine kinase receptors it is possible that an abnormality at this level could be the primary driver of pituitary tumorigenesis. The serine/threonine kinase B-Raf functions as a downstream effector of Ras, interpolated between the tyrosine kinase receptor and the mitogen-activated protein kinase (MAPK) pathway and acting in parallel to the Akt pathway. We have found significant over-expression of B-Raf mRNA in pituitary adenomas, specifically NFPAs and a positive correlation between mRNA and protein expression. B-Raf overexpression could lead to increased activation of the MAPK pathway. Using microarray we have found that the Bcl-associated athanogene (BAG1) mRNA is overexpressed in somatotroph adenomas and NFPAs; this oncogene binds to and activates Raf-1, which can potentiate B-Raf activity by heterodimerisation. In a pituitary protein array we have identified several over- and underexpressed proteins and one of the prominent differentially expressed proteins with potential importance in tumorigenesis was the heat shock protein 110 (HSP110). This showed significant overexpression in NFPAs and prolactinomas. Interestingly, another molecular chaperone, the aryl hydrocarbon receptor interactive protein (AIP) has been recently identified as a cause for pituitary adenomas in families with isolated pituitary tumours. We have identified 5 different mutations in 19 familial acromegalic families causing autosomal dominant disease with incomplete penetrance. We have also observed prominent differences in AIP mRNA and protein expression between normal pituitary cells and sporadic pituitary tumours. Previous data suggest that AIP acts as a tumour suppressor gene but the exact mechanism leading to pituitary tumorigenesis when AIP is lacking remains to be identified.