Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis

Gao, Y., Vincent, D., Davis, A. J., Sansom, O. , Bartholin, L. and Li, Q. (2016) Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis. Oncotarget, 7(27), pp. 40904-40918. (doi:10.18632/oncotarget.10149) (PMID:27344183)

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Abstract

Despite the well-established tumor suppressive role of TGFβ proteins, depletion of key TGFβ signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGFβ signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGFβ receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably, these mice developed ovarian sex cord-stromal tumors with complete penetrance, leading to reproductive failure and mortality. The tumors expressed multiple granulosa cell markers and caused elevated serum inhibin and estradiol levels, reminiscent of granulosa cell tumors. Consistent with the tumorigenic effect, overactivation of TGFBR1 altered tumor microenvironment by promoting angiogenesis and enhanced ovarian cell proliferation, accompanied by impaired cell differentiation and dysregulated expression of critical genes in ovarian function. By further exploiting complementary genetic models, we substantiated our finding that constitutively active TGFBR1 is a potent oncogenic switch in mouse granulosa cells. In summary, overactivation of TGFBR1 drives gonadal tumor development. The TGFBR1 constitutively active mouse model phenocopies a number of morphological, hormonal, and molecular features of human granulosa cell tumors and are potentially valuable for preclinical testing of targeted therapies to treat granulosa cell tumors, a class of poorly defined ovarian malignancies.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Vincent, Dr David and Sansom, Professor Owen
Authors: Gao, Y., Vincent, D., Davis, A. J., Sansom, O., Bartholin, L., and Li, Q.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncotarget
Publisher:Impact Journals
ISSN:1949-2553
ISSN (Online):1949-2553
Published Online:17 June 2016
Copyright Holders:Copyright © 2016 Impact Journals, LLC
First Published:First published in Oncotarget 7(27):40904-40918
Publisher Policy:Reproduced under a Creative Commons License

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