Natural and molecular history of prolactinoma: insights from aPrlr-/– mouse model

// Valérie Bernard 1 , Chiara Villa 2, 3 , Aurélie Auguste 4 , Sophie Lamothe 1 , Anne Guillou 5 , Agnès Martin 5 , Sandrine Caburet 6 , Jacques Young 1, 7, * , Reiner A. Veitia 6, * and Nadine Binart 1, * 1 Unité INSERM 1185, Faculté de Médecine Paris Sud, Université Paris-Saclay, le Kremlin-Bicêtre, France 2 Service d’Anatomie et Cytologie Pathologiques, Hôpital Foch, Suresnes, France 3 Institut Cochin, Unité INSERM 1016, CNRS UMR 8104, Université Paris Diderot, Paris, France 4 Unité INSERM 981, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France 5 Unité INSERM 1191, CNRS, Institut de Génomique Fonctionnelle, Montpellier, France 6 Institut Jacques Monod, Université Paris Diderot, Paris, France 7 APHP, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, le Kremlin-Bicêtre, France * Co-senior authors Correspondence to: Nadine Binart, email: nadine.binart@inserm.fr Keywords: prolactin receptor; prolactinoma; pituitary adenoma; transcriptomics; mouse model Received: June 22, 2017      Accepted: November 19, 2017      Published: December 27, 2017 ABSTRACT Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient ( Prlr –/– ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr –/– mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development. Prlr –/– females develop large secreting prolactinomas from 12 months of age, with a penetrance of 100%, mimicking human aggressive densely granulated macroprolactinoma, which is a highly secreting subtype. Mean blood PRL measurements reach 14 902 ng/mL at 24 months in Prlr –/– females while PRL levels were below 15 ng/mL in control mice ( p < 0.01). By comparing pituitary microarray data of Prlr –/– mice and an estrogen-induced prolactinoma model in ACI rats, we pinpointed 218 concordantly differentially expressed (DE) genes involved in cell cycle, mitosis, cell adhesion molecules, dopaminergic synapse and estrogen signaling. Pathway/gene-set enrichment analyses suggest that the transcriptomic dysregulation in both models of prolactinoma might be mediated by a limited set of transcription factors (i.e., STAT5, STAT3, AhR, ESR1, BRD4, CEBPD, YAP, FOXO1) and kinases (i.e., JAK2, AKT1, BRAF, BMPR1A, CDK8, HUNK, ALK, FGFR1, ILK). Our experimental results and their bioinformatic analysis provide insights into early genomic changes in murine models of the most frequent human pituitary tumor.