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.
Highlights
Sex cord-stromal tumors are derived from the granulosa, theca, and/or stromal fibroblast components of the ovary and represent ~8% of all categories of ovarian tumors [1]
The TGFBR1CA transgene was knocked into the hypoxanthine-guanine phosphoribosyltransferase (Hprt) locus, with a STOP sequence flanked by two Lox sites [22]
Signals of red fluorescent protein (RFP; a Gli1-Cre reporter) was mainly found in theca layers, Gli1-Cre activity was observed in a subset of granulosa cells within some follicles (Figure S7I and J) and signals were detected in granulosa cells and tumor tissues using TGFBR1 probe by RNAscope (Figure S7K-N) in tamoxifen-treated mice, suggesting potential overactivation of TGFBR1 in granulosa cell compartment
Summary
Sex cord-stromal tumors are derived from the granulosa, theca, and/or stromal fibroblast components of the ovary and represent ~8% of all categories of ovarian tumors [1]. The molecular etiology of sex cord-stromal tumors is poorly defined, partially because of its rarity and the fact that research efforts in ovarian cancer research field have been predominantly focused on tumors of epithelial cell origin, the major type of ovarian tumors [1]. There are several mouse models for sex cord-stromal tumors [4,5,6,7,8,9,10,11,12], such as mice with targeted deletion of α inhibin (Inha) [4], Smad1/5 [5], bone morphogenetic protein (BMP) type 1 receptors [6], www.impactjournals.com/oncotarget and forkhead box O1/3 (Foxo1/3) and phosphatase and tensin homolog (Pten) [12] and constitutive activation of wingless-type MMTV integration site (WNT)/β-catenin [7, 8]. The findings of Inha as a tumor suppressor gene specific for the gonad and adrenal and the inhibitory function of BMP receptors and SMADs in ovarian tumor formation reveal the importance of the transforming growth factor β (TGFβ) superfamily in gonadal carcinogenesis [4,5,6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
