This study evaluated menin protein localization in two murine models that develop non-MEN1 prolactinomas in a female-predominant manner: the dopamine D2-receptor knockout mouse and the hCGβ-subunit–overexpressing mouse. Using immunostaining, the authors found that lactotrophs within prolactinomas exhibited a marked loss of nuclear MEN1 signal, with protein redistributed to the cytoplasm. By contrast, pituitaries from male mice retained nuclear MEN1 localization irrespective of genotype. These observations indicate that in the tumour context menin is excluded from the nucleus in affected female lactotrophs, suggesting a change in subcellular distribution rather than in gene expression.
Pituitary Men1 mRNA levels were measured by qPCR across genotypes and sexes. The authors report that Men1 expression remained unchanged despite genotype or tumour status in both male and female mice. This finding supports the conclusion that a functional MEN1 deficiency in these non-MEN1 prolactinomas is not due to decreased Men1 transcription but instead to altered subcellular localization of the MEN1 protein.
Loss of nuclear menin in murine prolactinomas was associated with multiple alterations in regulators of cell proliferation and survival. Specifically, tumours that showed MEN1 nuclear exclusion had reduced expression of the cell-cycle inhibitor p27 and the tumour suppressor Pten, increased expression of Ccnd1 (cyclin D1), and enhanced levels of phosphorylated AKT (pAKT). These molecular changes are consistent with activation of proliferative and pro-survival pathways and with impairment of tumour suppressor signalling in lactotrophs where MEN1 is excluded from the nucleus.
The authors used in vivo pharmacologic and surgical approaches to test whether menin localization is responsive to dopaminergic and hormonal stimuli. Treatment with a dopamine-agonist preserved nuclear MEN1 localization in lactotrophs, whereas dopamine blockade promoted nuclear loss of menin. Similarly, exposure to estradiol induced menin nuclear exclusion. These experimental manipulations link dopaminergic signalling and estradiol to the subcellular distribution of MEN1 protein and imply that endocrine and pharmacologic environments can influence whether menin resides in the nucleus or is sequestered in the cytoplasm.
Analysis of human pituitary tissue corroborated the murine observations. In normal human pituitaries, lactotrophs showed both nuclear and cytoplasmic menin localization. In prolactinomas from patients who had received dopamine-agonist therapy, menin localization included preserved nuclear signal. In a reported prolactinoma from an untreated female patient, nuclear menin was partially lost. These human biopsy data support the concept that nuclear exclusion of menin can occur in sporadic prolactinomas and that dopaminergic therapy is associated with preserved nuclear localization.
Collectively, the results identify a state of functional MEN1 deficiency in sporadic prolactinomas that is driven by nuclear exclusion of menin rather than loss of MEN1 expression. Nuclear exclusion correlated with reduced tumour suppressor signalling (p27, Pten), increased proliferative drivers (Ccnd1), and elevated pAKT, linking menin mislocalization to pathways known to support tumour development and growth. The findings suggest that restoring nuclear menin localization may represent a therapeutic strategy; the authors note that dopamine-agonist treatment preserved nuclear MEN1 in vivo, whereas dopamine blockade and estradiol induced its exclusion. Details of therapeutic approaches specifically aimed at re-establishing nuclear menin beyond dopamine-agonist effects were not reported in the source.
Limitations noted by the authors in the preprint context include that the work is derived from animal models and a limited set of human biopsies, and the manuscript is a preprint not yet peer reviewed. The source did not report clinical outcome data or detailed methods beyond those summarized here, and no competing interests were declared.
Overall, this study supports a model in which subcellular mislocalization of menin produces a functional MEN1-deficient state that contributes to sporadic prolactinoma pathogenesis and identifies preservation or restoration of nuclear menin as a mechanistically informed potential therapeutic angle.