Global expression profiling of sex cord stromal tumors from Men1 heterozygous mice identifies altered TGF-β signaling, decreased Gata6 and increased Csf1r expression

Queensland Institute of Medical Research, QLD, Australia.
International Journal of Cancer (Impact Factor: 5.01). 03/2009; 124(5):1122-32. DOI: 10.1002/ijc.24057
Source: PubMed

ABSTRACT Heterozygous disruption of the Men1 gene predisposes mice to the development of multiple endocrine tumors, accurately mimicking the human MEN1 cancer predisposition syndrome. Additionally, Men1(+/-) mice frequently develop sex cord adenomas. The mechanism underlying the susceptibility of these mice to sex cord tumor development has not been fully determined, but data suggest it may involve transcriptional regulation of key growth promoting/repressing genes. To identify potential menin-regulated genes that may be important for tumor suppression in sex cord cells, we compared the global gene expression profiles of testis and ovary adenomas with other endocrine tumors of the pancreas and pituitary from Men1 heterozygous mice and with control tissues. Gonadal tumors clustered separately from pancreas and pituitary tumors with only a few genes (e.g., Cdkn2c) commonly dysregulated in all tumor types. Testis and ovary tumors displayed a higher level of transcriptional similarity to each other than they did to their respective control tissues. Among genes that had decreased expression in tumors was significant over-representation of genes associated with the TGF-beta, hedgehog and Wnt signaling, indicating that loss of menin function affects these pathways at the level of transcription. Aberrant protein expression in Leydig and granulosa cells of 2 transcriptionally dysregulated gene products, Gata6 and Csf1r were confirmed by immunohistochemistry. We propose that sex cord tumor susceptibility in Men1(+/-) mice involves deregulated cell proliferation due to dysregulation of multiple cell growth regulating genes including: reduced Cdkn2c transcription, loss of TGF-beta pathway tumor suppressor function (e.g., Gata6) and transcriptional activation of Csf1r.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Wnt signalling is activated in both pituitary organogenesis and its mature function. Wnt ligands and Wnt signalling pathways are critical for the regulation of the formation of the pituitary. In the mature pituitary, Wnt signalling pathways control cell activity and may stimulate cell proliferation in both physiological and pathological processes. This review compares Wnt signalling pathways active in the developing and mature pituitary and explores how this gives us further insight into the development of pituitary adenomas.
    Endocrine Related Cancer 05/2013; 20(3):R101-R111. DOI:10.1530/ERC-13-0005 · 4.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Homeobox genes encode transcription factors that have well-established roles in embryonic development. We recently discovered the Rhox genes, a new family of homeobox genes, which are selectively expressed in the developing embryo, postnatal and adult gonads, and accessory tissues associated with mammalian reproduction. The largest and best-characterized Rhox cluster is found in mouse. However, all mammals examined to date possess a set of Rhox genes that, while they may vary in number by species, appear relevant to reproduction and are located in the syntenic region of the X chromosome. Rhox5, the founding member of the family, was initially cloned from a screen to identify tumorigenic antigens from T-cell lymphomas, and was later found to be widely expressed in tumors from tissues of diverse origins that do not normally express the Rhox genes. This aberrant upregulation appears to be a general feature of many Rhox genes, but the implications of this misexpression remain largely uninvestigated. In this review, we will discuss the latest findings on the normal and abnormal roles of the Rhox genes and their potential contributions to the formation and progression of tumors.
    Frontiers in Bioscience 01/2013; 18:474-92. DOI:10.2741/4115 · 4.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) is characterized by tumors of the parathyroid, enteropancreas, and anterior pituitary. The MEN1 gene encodes the tumor suppressor menin of 610 amino acids that has multiple protein partners and activities. The particular pathways that, when lost, lead to tumorigenesis are not known. We demonstrated that members of a three-generation MEN1 kindred are heterozygous for a donor splice site mutation at the beginning of intron 3 (IVS3 + 1G→A). Lymphoblastoid cells of a mutant gene carrier had, in addition to the wild-type menin transcript, an aberrant transcript resulting from use of a cryptic splice site within exon III that splices to the start of exon IV. The predicted menin Δ(184-218) mutant has an in-frame deletion of 35 amino acids but is otherwise of wild-type sequence. The transfected menin Δ(184-218) mutant was well expressed and fully able to mediate the normal inhibition of the activity of the transcriptional regulators JunD and NF-κB. However, it was defective in mediating TGF-β-stimulated Smad3 action in promoter-reporter assays in insulinoma cells. Importantly, lymphoblastoid cells from an individual heterozygous for the mutation had reduced TGF-β-induced (Smad3) transcriptional activity but normal JunD and NF-κB function. In addition, the mutant gene carrier lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF-β than cells from an unaffected family member. In conclusion, the menin mutant exhibits selective loss of the TGF-β signaling pathway and loss of cell proliferation control contributing to the development of MEN1.
    Journal of Biological Chemistry 01/2012; 287(11):8584-97. DOI:10.1074/jbc.M112.341958 · 4.60 Impact Factor