Global expression profiling of sex cord stromal tumors fromMen1heterozygous mice identifies altered TGF‐β signaling, decreased Gata6 and increased Csf1r expression

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‐β, 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‐β pathway tumor suppressor function (e.g., Gata6) and transcriptional activation of Csf1r. © 2008 Wiley‐Liss, Inc.

Frequent Promoter Hypermethylation of the APC and RASSF1A Tumour Suppressors in Parathyroid Tumours

“…Furthermore, parafibromin has been shown to associate with the Wnt oncoprotein β-catenin and to down-regulate c-Myc oncogene transcription through direct binding to the c-Myc promoter region, supporting the role of parafibromin as a tumor suppressor protein that inhibits Wnt signaling [7]. Interestingly, the MEN1 product menin was also coupled to the Wnt pathway, demonstrated by its epigenetic regulation of Axin2 and by expression profiling of MEN1 knock-out mice [8]–[9].…”

Wnt signalling in pituitary development and tumorigenesis

“…In these tumours, there was a down-regulation of Wnt4, Wnt9a, Fz6/Fzd6 and Lrp2, although in this study, pituitary tumours were not specifically examined (Mould et al 2009). …”

“…Mouse Down-regulation of Wnt4, Wnt9a, Fz6 and Lrp2, but pituitaries not specifically examined Mould et al (2009) Carney complex Mouse …”

Juvenile Granulosa Cell Tumor of the Testicle – Report of a Neonatal Case with Positive Alpha-fetoprotein Immunohistochemical Staining

“…For example, findings on electron microscopy such as dual epithelial-smooth muscle differentiation, similarity to primitive Sertoli cells and pre-ovulatory granulosa cells, granulosa cells with continuous basal lamina, and cytoplasmic filaments with evenly distributed dense bodies resembling smooth muscle, may be definitive 3, 4. Additionally, molecular markers such as cytoplasmic expression of SOX9 or dysregulated immunohistologic expression of GATA6 and CSF1R could also be helpful 5, 6…”