Endocrine Abstracts

JOINT3697

Menin is a fundamental protein for regulating the cell cycle and proliferation in the pituitary gland, specifically in lactotroph function due to its ability to regulate p27Kip1 and the AKT signalling pathway. In this work, we focused on the involvement of menin on prolactinoma development, using two murine models of prolactinoma. One model is characterised by overexpressing the β subunit of the human chorionic gonadotropic hormone (hCGβ+) and the other by being knock-out for the dopamine receptor type 2 (Drd2KO). In both models, only females develop lactotroph hyperplasia and hyperprolactinemia from three months of age. In the hCGβ+ murine model, but not in the Drd2KO, we observed, by RTqPCR, higher levels of expression of the MEN1 gene in the pituitary gland of males than in females, without genotypic differences. We performed double confocal immunofluorescence to analyse the expression of proteins of interest specifically in lactotrophs (colocalization). Although no differences were detected between sexes or genotypes in the percentage of menin+ lactotrophs, important changes were observed in the subcellular localisation of menin. In WT male and female lactotrophs, menin is found in both, cytoplasm and nucleus. However, in transgenic females from both models (prolactinomas), nuclear expression of menin is completely lost. This lack of nuclear menin correlates with a decrease in the percentage of p27+ lactotrophs, accompanied by a marked increase in the levels of pAKT expression and a lower level of PTEN expression in the tumoral pituitary glands of both models compared to WT females. These alterations were not observed in males whose pituitary glands retained stable expression of nuclear menin and high levels of PTEN. We conclude that the loss of the nuclear menin in lactotrophs from transgenic females and the lower expression of PTEN contribute to the decreased expression of p27 and the elevated levels of pAKT respectively, favouring the development of a prolactinoma.