MENX.

Multiple endocrine neoplasias (MEN) are a group of hereditary disorders characterized by tumors arising in more than one neuroendocrine tissue. There are two major forms which can occur in humans, MEN type 1 (MEN1) and MEN type 2 (MEN2). These syndromes are transmitted as autosomal dominant traits with high penetrance and have a different tumor spectrum. MEN1 and MEN2 are caused by germline mutations in the MEN1 and RET genes, respectively. Recently, a variant of the MEN syndromes was discovered in a rat colony and was named MENX since affected animals develop tumors with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Extensive genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, heterozygous germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized which is caused by mutations in p27. Altogether these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here I review the phenotypic features and the genetics of the MENX rat syndrome. I briefly address the main functions of p27 and how they are affected by the MENX-associated mutation. Finally, I present examples of how this animal model might be exploited as a translational platform for preclinical studies of pituitary adenomas

Multiple endocrine neoplasia syndromes associated with mutation of p27.

Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Until recently two MEN syndromes were known, i.e. the MEN type 1 (MEN1) and type 2 (MEN2), which are caused by germline mutations in the MEN1 and RET genes, respectively. These two syndromes are characterized by a different tumor spectrum. A few years ago we described a variant of the MEN syndromes, which spontaneously developed in a rat colony and was named MENX. Affected animals consistently develop multiple endocrine tumors, with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized, which is caused by heterozygous mutations in p27. These studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here we review the characteristics of the MENX and MEN4 syndromes and we briefly address the main function of p27 and how it is affected by MENX- or MEN4-associated mutations

Animal models of MEN1.

Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the human MEN1 gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation in Cdkn1b (p27) and not in Men1 Both Men1-knockout mice and MENX rats have been exploited for therapy-response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors

CDKN1B (p27) defects leading to pituitary tumors.

In recent years, new insight into the etiopathogenesis of hereditary pituitary tumors has emerged. Several novel susceptibility genes for these tumors have been identified and among them is CDKN1B encoding the cell cycle regulator p27. Heterozygous germline mutations in CDKN1B are associated with the predisposition to multiple neuroendocrine tumors (NETs), including pituitary tumors. Patients carrying these mutations are affected by the Multiple Endocrine Neoplasia type 4 (MEN4) syndrome. In this chapter, we discuss the current state of knowledge of the function of p27; present clinical and basic findings related to the pituitary phenotype of MEN4 patients as well as the functional characterization of the CDKN1B mutations identified in these patients

Multiple endocrine neoplasia type 4.

A few years ago a novel multiple endocrine neoplasia syndrome, named multiple endocrine neoplasia type 4 (MEN4), was discovered thanks to studies conducted on a MEN syndrome in the rat (named MENX). The rat and the human syndromes are both caused by germline mutations in the Cdkn1b/CDKN1B gene, respectively. This gene encodes p27Kip1, a putative tumor suppressor which binds to and inhibits cyclin/cyclin-dependent kinase complexes, thereby preventing cell cycle progression. MEN4 patients carry heterozygous mutations at various residues of p27Kip1 and present with endocrine lesions mainly belonging to a MEN1-like spectrum: their most common phenotypic features are parathyroid and pituitary adenomas. Recently, germline mutations in p27kip1 were also identified in patients with a sporadic parathyroid disease presentation. In vitro functional analysis of several CDKN1B sequence changes identified in MEN4 patients detected impaired activity of the encoded p27Kip1 variant proteins (e.g. reduced expression, mislocalization or poor binding to interaction partners), thereby highlighting the characteristics of the protein which are critical for tumor suppression. Although the number of MEN4 patients is low, the discovery of this syndrome has demonstrated a novel role for CDKN1B as a tumor susceptibility gene for neuroendocrine tumors. Here, we review the clinical characteristics of the MEN4 syndrome and the molecular phenotype of the associated p27Kip1 mutations

Multiple endocrine neoplasia type 4 (MEN 4).

In this chapter, the more recently identified syndrome multiple endocrine neoplasia type 4 (MEN 4) is described. The current knowledge regarding the clinical spectrum including primary hyperparathyroidism, pituitary adenomas, neuroendocrine neoplasms (NENs), and other endocrine and non-endocrine tumors is presented. Since the genetic cause is known, one paragraph focuses on genetic counseling of these patients. With regard to the treatment, particular emphasis has been put on surgical aspects

Animal models of multiple endocrine neoplasia.

Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant diseases with high penetrance characterized by proliferative lesions (usually hyperplasia or adenoma) arising in at least two endocrine tissues. Four different MEN syndromes have been so far identified: MEN type 1 (MEN1), MEN2A (also referred to as MEN2), MEN2B (or MEN3) and MEN4, which have slightly varying tumor spectra and are caused by mutations in different genes. MEN1 associates with loss-of-function mutations in the MEN1 gene encoding the tumor suppressor menin. The MEN2A and MEN2B syndromes are due to activating mutations in the proto-oncogene RET (Rearranged in Transfection) and are characterized by different phenotypic features of the affected patients. MEN4 was the most recent addition to the family of the MEN syndromes. It was discovered less than 10 years ago thanks to studies of a rat strain that spontaneously develops multiple endocrine tumors (named MENX). These studies identified an inactivating mutation in the Cdkn1b gene, encoding the putative tumor suppressor p27, as the causative mutation of the rat syndrome. Subsequently, germline mutations in the human ortholog CDKN1B were also found in a subset of patients with a MEN-like phenotype and this led to the identification of MEN4. Small animal models have been instrumental in understanding important biochemical, physiological and pathological processes of cancer onset and spread in intact living organisms. Moreover, they have provided us with insight into gene function(s) and molecular mechanisms of disease progression. We here review the currently available animal models of MEN syndromes and their impact on the elucidation of the pathophysiology of these diseases, with a special focus on the rat MENX syndrome that we have been characterizing

p27kip1: A new multiple endocrine neoplasia gene?

Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two types of MEN syndromes have long been known: MEN type 1 (MEN1) and MEN type 2 (MEN2), associated with a different spectrum of affected organs. MEN1 and MEN2 are caused by germline mutations in the MEN1 tumor suppressor gene and the RET proto-oncogene, respectively. Lately, a new type of MEN was identified (named MEN4) which is due to mutations in the CDKN1B gene, encoding for p27kip1 (p27), a cyclin-dependent kinase (Cdk) inhibitor that regulates the transition of cells from G1 to S phase. p27 is a non-canonical tumor suppressor since it is usually not somatically mutated in human cancers but it is often downregulated by post-translational mechanisms. The discovery of MEN4 has defined a new role for CDKN1B as a tumor susceptibility gene for multiple endocrine tumors. To date, six germline CDKN1B mutations have been found in patients with a MEN1-like phenotype but negative for MEN1 mutations. Due to the limited number of patients so far identified, the phenotypic features of MEN4 are not clearly defined. Here, we review the clinical and molecular characteristics of the MEN4 syndrome and summarize the main functions of p27 to better comprehend how their alteration can predispose to neuroendocrine tumors

The MENX syndrome and p27: Relationships with multiple endocrine neoplasia.

In the past 3 years new insight into the etiopathogenesis of hereditary endocrine tumors has emerged from studies conducted on MENX, a rat multiple endocrine neoplasia (MEN) syndrome. MENX spontaneously developed in a rat colony and was discovered by serendipity when these animals underwent complete necropsy, as they were found to consistently develop multiple endocrine tumors with a spectrum similar to both MEN type 1 (MEN1) and MEN2 human syndromes. Genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for the MENX syndrome. Capitalizing on these findings, we and others identified heterozygous germline mutations in the human homologue, CDKN1B, in patients with multiple endocrine tumors. As a consequence of these observations a novel human MEN syndrome, named MEN4, was recognized which is caused by mutations in p27. Altogether these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. In this chapter we present the MENX syndrome and its phenotype, and we compare it to the human MEN syndromes; we discuss the current state of knowledge regarding the genes associated to inherited MEN, with a particular focus on CDKN1B; we present recent clinical and basic findings about the MEN4 syndrome and the functional characterization of the CDKN1B mutations identified. These findings are placed in the broader context of how p27 dysregulation might affect neuroendocrine cell function and trigger tumorigenesis