Journal Article

The Müllerian inhibiting substance type 2 receptor suppresses tumorigenesis in testes with sustained β-catenin signaling

Pradeep S. Tanwar, Arno E. Commandeur, LiHua Zhang, Makoto M. Taketo and Jose M. Teixeira

in Carcinogenesis

Volume 33, issue 12, pages 2351-2361
Published in print December 2012 | ISSN: 0143-3334
Published online September 2012 | e-ISSN: 1460-2180 | DOI:
The Müllerian inhibiting substance type 2 receptor suppresses tumorigenesis in testes with sustained β-catenin signaling

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Dysregulated WNT/β-catenin signaling in murine testes results in a phenotype with complete germ cell loss that resembles human Sertoli cell-only syndrome. In other systems, including the ovary, dysregulated WNT/β-catenin induces tumorigenesis but no tumors are observed in the mutant testes without deletion of a tumor suppressor, such as phosphatase and tensin homolog (PTEN). Müllerian inhibiting substance (MIS, also known as AMH), a member of the transforming growth factor-β family of growth factors responsible for Müllerian duct regression in fetal males, has been shown to inhibit tumor growth in vitro and in vivo but its role as an endogenous tumor suppressor has never been reported. We have deleted the MIS type 2 receptor (MISR2), and thus MIS signaling, in mice with dysregulated WNT/β-catenin and show that these mice develop testicular stromal tumors with 100% penetrance within a few months postnatal. The tumors are highly proliferative and have characteristics of either Sertoli cell tumors or progenitor Leydig cell tumors based on their marker profiles and histology. Phosphorylated Sma and mothers against decapentaplegic-related homolog 1/5/8 is absent in the tumors and β-catenin target genes are induced. The tumor suppressor TP53 is also highly expressed in the tumors, as is phosphorylated γH2AX, which is indicative of DNA damage. The phenotype of these tumors closely resembles those observed when PTEN is also deleted in mice with dysregulated WNT/β-catenin. Tumorigenesis in these mice provides conclusive evidence that physiological MIS signaling is a tumor suppressor mechanism and suggests that targeted treatment of MISR2-expressing cancers with therapeutic MIS should have a beneficial effect on tumor progression.

Journal Article.  7207 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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