SFEBES2014 Oral Communications Pituitary (6 abstracts)
Increased frequency and earlier onset of pituitary tumours in mice deleted for a multiple endocrine neoplasia type 1 allele and null for prolyl hydroxylase domain protein 1 (Men1+/−/Phd1−/−)
Mark Stevenson , Sian Piret , Mahsa Javid , Tammie Bishop , Anita Reed , Gerard Walls , Katie Gaynor , Paul Newey , Paul Christie , Lynn Nicholls , Peter Ratcliffe & Rajesh Thakker
University of Oxford, Oxford, UK.
Cumulative genetic abnormalities within an oncogenic pathway may contribute to earlier onset or increased aggressiveness of cancers. An example in human and murine cancer is the dysregulation of Wnt signalling by inactivation of the adenomatous polyposis coli (APC) gene that results in accumulation of nuclear β-catenin and earlier onset of renal cell carcinoma, which can be accelerated by p53-deficiency. We therefore investigated the effects of such cumulative genetic abnormalities in the development of neuroendocrine tumours (NETs), which occur as part of multiple endocrine neoplasia type 1 (MEN1), associated with pancreatic NETs, pituitary NETs and parathyroid tumours; and von Hippel Lindau (VHL) syndrome associated with pancreatic NETs, phaeochromocytomas, renal cancers and haemangioblastomas of the retina and CNS. MEN1 includes mutation of the Men1 gene that encodes menin, a tumour suppressor regulating transcription and genome stability; and VHL tumour development involves a tumour suppressor pathway, including hypoxia-inducible factor-1α (HIF-1α) that is post-translationally modified by prolyl hydroxylase domain proteins (PHDs) to promote HIF-1α ubiquitination and proteosomal degradation. To investigate for cumulative effects we interbred Men1+/−/PHD1+/− mice and studied them for development of NETs. A total of 108 mice comprising 62 Men1+/−/PHD1+/+ and 46 Men1+/−/Phd1−/− mice were generated and by 9–12 months of age pituitary tumours, which consisted of prolactinomas and somatotrophinomas with loss of menin expression, had developed in 12 of 46 (26.1%) Men1+/−/Phd1−/− mice compared with four of 62 (6.5%) Men1+/− PHD1+/+ mice (P<0.01). Furthermore pituitary tumour development occurred earlier in Men1+/−/Phd1−/− mice such that four of 24 (16.7%) mice had tumours at 9 months of age compared with zero of 38 (0%) Men1+/−/PHD1+/+ mice (P<0.02). Pancreatic NET development in both groups was similar. Thus, our studies show that loss of Men1 and PHD1 may act in an additive manner to result in earlier onset and increased frequency of pituitary tumours.
Volume 34
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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