Endocrine Abstracts (2019) 65 OC2.2 | DOI: 10.1530/endoabs.65.OC2.2

Investigating the role of AIP in pituitary tumourigenesis

Anisha Mistry1, Antonia Solomou1,2, Maria Lillina Vignola1,2, Chung Thong Lim1, Maria Herincs1, Francisca Caimari1,3, Alejandro Ibáñez Costa1,4, Federica Begalli1,5, Angelica Gualtieri1, Federico Roncaroli6, Karine Rizzoti7, Carles Gaston-Massuet1 & Márta Korbonits1


1Queen Mary University, London, UK; 2Kings College London, London, UK; 3University College London, London, UK; 4Maimondes Biomedical Research Institute, Andalusia, Spain; 5Imperial College London, London, UK; 6The University of Manchester, Manchester, UK; 7The Francis Crick Institute, London, UK


Introduction: Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to growth hormone (GH, 90% of patients) or prolactin (PRL)-secreting tumours, with negligible number of patients with other pituitary tumour types. Animal models of acromegaly are scarce and Aip models have controversial data. Therefore we have generated two pituitary-specific Aip knockout mouse models to study the consequences of loss of AIP protein and understand its role in tumourigenesis.

Models and phenotype: Our AipFlox/Flox;Hesx1Cre/+ model abrogates Aip in cells expressing the early pituitary transcription factor Hesx1, specifically targeting the anterior pituitary cells from E8.5. The inducible AipFlox/Flox;Sox2CreERT2/+ model deletes Aip upon administration of tamoxifen exclusively in Sox2-expressing cells, which form the pituitary stem-cell niche.

Results: The AipFlox/Flox;Hesx1Cre/+ model mirrors the human phenotype, showing an increased body size, enlarged organs (e.g. heart), high circulating IGF-1 and 85% penetrance of functional pituitary tumours at 15 months. Contrastingly, the tamoxifen-inducible Sox2-based model showed no increased body size or altered IGF-1 up to 18 months from injecting at 3 or 8 weeks old. A developmental abnormality localised in the pituitary intermediate lobe (IL) is observed in at least 50% of AipFlox/Flox;Hesx1Cre/+ embryos and tamoxifen-injected AipFlox/Flox;Sox2CreERT2/+ adults. Furthermore, tamoxifen-injection during pregnancy resulted in embryonic IL abnormality, recapitulating the AipFlox/Flox;Hesx1Cre/+ embryonic phenotype. The observed abnormality consists of ectopic PIT-1, GH and PRL-expressing cells in the IL Moreover, some of the tumours in adult animals arise from these altered cells of the IL.

Conclusions: Our data suggest that Aip loss leads to a pituitary development defect with ectopically expressed GH and PRL, ultimately promoting tumourigenesis. This supports the clinical observations, that AIP mutation positive patients invariably develop disease during childhood and there is a lack of somatic AIP mutations in pituitary tumours. Overall, this highlights AIP’s key role in tumours and normal pituitary development.