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

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.

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

“…The data reported in this study (summarized in Fig. 8), together with former observations from us and several other groups [2, 39, 51, 54-57], support a new concept for the pathogenesis of prolactinomas. We suggest that PRLR signaling, involving the PRLR per se or effectors thereof, may favor a state of PRL resistance resulting in the downregulation of proapoptotic and antiproliferative effects that are mandatory for pituitary homeostasis, thereby promoting tumor development.…”

“…Of interest, it has been proposed that a loss-of-function PRLR mutation leads to hyperprolactinemia [53]. In addition, recent studies in PRLR-deficient female mice showed that cabergoline, a dopamine receptor 2 agonist, potently suppressed hyperprolactinemia but did not induce tumor shrinkage after 3 months of treatment [54], suggesting that PRLR activity is necessary for the control of lactotrope cell turnover. In fact, prolactinomas are currently being revisited as “pathologies of signaling pathways” [51].…”

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas

“…PRL has been shown to promote the proliferation and differentiation of various types of cancer cells 16 , 25 . It does so by activating associated signaling pathways via JAK2 phosphorylation of signal transducers and activators of transcription (STAT), protein kinase C and phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) in cells that express PRLR 16 , 39 - 41 .…”

“…PRL has been shown to promote the proliferation and differentiation of various types of cancer cells 16 , 25 . It does so by activating associated signaling pathways via JAK2 phosphorylation of signal transducers and activators of transcription (STAT), protein kinase C and phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) in cells that express PRLR 16 , 39 - 41 . Although the majority of prolactinomas express both PRLR and ERα 13 , 16 , 29 , 35 , to the best of our knowledge, the effects of PRL on prolactinoma cell ERα signaling are yet to be elucidated.…”

“…It does so by activating associated signaling pathways via JAK2 phosphorylation of signal transducers and activators of transcription (STAT), protein kinase C and phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) in cells that express PRLR 16 , 39 - 41 . Although the majority of prolactinomas express both PRLR and ERα 13 , 16 , 29 , 35 , to the best of our knowledge, the effects of PRL on prolactinoma cell ERα signaling are yet to be elucidated. Thus in the present study, HPA cells were starved of serum and estrogen for 24 h, and then treated with 20 ng/ml PRL for 4 h. Western blot analysis revealed a significant upregulation in pERα, pJAK2, pAKT, pERK, pSTAT5 and PRLR expression following PRL administration.…”