Oncotarget

Priority Research Papers:

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

Yang Gao, David F. Vincent, Anna Jane Davis, Owen J. Sansom, Laurent Bartholin and Qinglei Li _

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Oncotarget. 2016; 7:40904-40918. https://doi.org/10.18632/oncotarget.10149

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Abstract

Yang Gao1, David F. Vincent3, Anna Jane Davis1, Owen J. Sansom3, Laurent Bartholin2 and Qinglei Li1

1 Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

2 Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Lyon, France

3 Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, United Kingdom

Correspondence to:

Qinglei Li, email:

Keywords: TGFβ, TGFBR1, tumor, ovary, mouse model

Received: April 01, 2016 Accepted: June 06, 2016 Published: June 17, 2016

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.


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