Constitutive Activation of Beta-Catenin in Uterine Stroma and Smooth Muscle Leads to the Development of Mesenchymal Tumors in Mice

Harvard University, Cambridge, Massachusetts, United States
Biology of Reproduction (Impact Factor: 3.32). 05/2009; 81(3):545-52. DOI: 10.1095/biolreprod.108.075648
Source: PubMed


Leiomyomas and other mesenchymally derived tumors are the most common neoplasms of the female reproductive tract. Presently, very little is known about the etiology and progression of these tumors, which are the primary indication for hysterectomies. Dysregulated WNT signaling through beta-catenin is a well-established mechanism for tumorigenesis. We have developed a mouse model that expresses constitutively activated beta-catenin in uterine mesenchyme driven by the expression of Cre recombinase knocked into the Müllerian-inhibiting substance type II receptor promoter locus to investigate its effects on uterine endometrial stroma and myometrium. These mice show myometrial hyperplasia and develop mesenchymal tumors with 100% penetrance that exhibit histological and molecular characteristics of human leiomyomas and endometrial stromal sarcomas. By immunohistochemistry, we also show that both transforming growth factor beta and the mammalian target of rapamycin are induced by constitutive activation of beta-catenin. The prevalence of the tumors was greater in multiparous mice, suggesting that their development may be a hormonally driven process or that changes in uterine morphology during pregnancy and after parturition induce injury and repair mechanisms that stimulate tumorigenesis from stem/progenitor cells, which normally do not express constitutively activated beta-catenin. Additionally, adenomyosis and endometrial gland hyperplasia were occasionally observed in some mice. These results show evidence suggesting that dysregulated, stromal, and myometrial WNT/beta-catenin signaling has pleiotropic effects on uterine function and tumorigenesis.

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    • "Taken together, these studies support a dual role for WNT/β-catenin signaling in MD biology, one for regression in males and another for differentiation in females. We have shown that either conditional knockout of β-catenin or constitutive activation of β-catenin in the MD mesenchyme leads to myometrial pathologies in female mice (Arango et al., 2005; Tanwar et al., 2009) and that constitutive activation of β-catenin in the MD mesenchyme predisposes male mice to focal MD retention (Tanwar et al., 2010). Thus, it appears that the contradictory finding that MD retention in males with either β-catenin knockout (Kobayashi et al., 2011) or constitutive activation of β-catenin (Tanwar et al., 2010) using the same Misr2-driven Cre would suggest that MD regression is exquisitely sensitive to WNT/ β-catenin signaling in the MD mesenchyme or that highly localized microenvironmental factors that modulate WNT/β-catenin signaling might need to act in concert with β-catenin to complete MD regression in males. "
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    ABSTRACT: A key event during mammalian sexual development is regression of the Müllerian ducts (MDs) in the bipotential urogenital ridges (UGRs) of fetal males, which is caused by the expression of Müllerian inhibiting substance (MIS) in the Sertoli cells of the differentiating testes. The paracrine signaling mechanisms involved in MD regression are not completely understood, particularly since the receptor for MIS, MISR2, is expressed in the mesenchyme surrounding the MD, but regression occurs in both the epithelium and mesenchyme. Microarray analysis comparing MIS signaling competent and Misr2 knockout embryonic UGRs was performed to identify secreted factors that might be important for MIS-mediated regression of the MD. A seven-fold increase in the expression of Wif1, an inhibitor of WNT/β-catenin signaling, was observed in the Misr2-expressing UGRs. Whole mount in situ hybridization of Wif1 revealed a spatial and temporal pattern of expression consistent with Misr2 during the window of MD regression in the mesenchyme surrounding the MD epithelium that was absent in both female UGRs and UGRs knocked out for Misr2. Knockdown of Wif1 expression in male UGRs by Wif1-specific siRNAs beginning on embryonic day 13.5 resulted in MD retention in an organ culture assay, and exposure of female UGRs to added recombinant human MIS induced Wif1 expression in the MD mesenchyme. Knockdown of Wif1 led to increased expression of β-catenin and its downstream targets TCF1/LEF1 in the MD mesenchyme and to decreased apoptosis, resulting in partial to complete retention of the MD. These results strongly suggest that WIF1 secretion by the MD mesenchyme plays a role in MD regression in fetal males.
    Preview · Article · Dec 2013 · Developmental Biology
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    • "Increased expression of aromatase [46], and alterations of the estrus cycle [47] due to the inactivation of Brca1 may have collectively led to increased levels of estrogen [47] contributing to the observed changes in the OSE. While this model may seem unique, other examples in the female reproductive tract of genetic change in one compartment leading to hyperplasia or tumorigenesis in a second compartment have been reported recently [48,49]. "
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    ABSTRACT: The development of genetically engineered models (GEM) of epithelial ovarian cancer (EOC) has been very successful, with well validated models representing high grade and low grade serous adenocarcinomas and endometrioid carcinoma (EC). Most of these models were developed using technologies intended to target the ovarian surface epithelium (OSE), the cell type long believed to be the origin of EOC. More recent evidence has highlighted what is likely a more prevalent role of the secretory cell of the fallopian tube in the ontogeny of EOC, however none of the GEM of EOC have demonstrated successful targeting of this important cell type. The precise technologies exploited to develop the existing GEM of EOC are varied and carry with them advantages and disadvantages. The use of tissue specific promoters to model disease has been very successful, but the lack of any truly specific OSE or oviductal secretory cell promoters makes the outcomes of these models quite unpredictable. Effecting genetic change by the administration of adenoviral vectors expressing Cre recombinase may alleviate the perceived need for tissue specific promoters, however the efficiencies of infection of different cell types is subject to numerous biological parameters that may lead to preferential targeting of certain cell populations. One important future avenue of GEM of EOC is the evaluation of the role of genetic modifiers. We have found that genetic background can lead to contrasting phenotypes in one model of ovarian cancer, and data from other laboratories have also hinted that the exact genetic background of the model may influence the resulting phenotype. The different genetic backgrounds may modify the biology of the tumors in a manner that will be relevant to human disease, but they may also be modifying parameters which impact the response of the host to the technologies employed to develop the model.
    Full-text · Article · Nov 2012 · Journal of Ovarian Research
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    • "Tanwar et al. (2009) employed the Amhr2 (Amh type 2 receptor) promoter to drive Cre expression (Amhr2 Cre/+ ) and activate β-catenin expression in mesenchymal cells surrounding the developing Müllerian ducts. This approach resulted in myometrial hyperplasia, adenomyosis, and mesenchymal tumors similar to leiomyomas and endometrial stromal sarcomas (Tanwar et al., 2009). Furthermore, hyperplasia of endometrial glands was occasionally observed suggesting that mesenchymal activation of Wnt/β-catenin signalling plays a role in the early events which may lead to endometrial carcinogenesis. "
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    ABSTRACT: The WNT signal transduction pathway plays a rate limiting role in early development of many different organs. To study the functional consequences of constitutive activation of the canonical WNT pathway in the developing uterus, we generated a novel mouse model where loss of the tumor suppressor gene Apc was induced. A mouse model was generated and evaluated where Amhr2(Cre/+) driven loss of Apc exon 15 was induced. The Apc recombination was detected mainly in the myometrial layer of the adult uterus. A significant loss of muscle fibers in myometrium was apparent, though with very few muscle cells earmarked by nuclear β-catenin. The finding was confirmed in the Pgr(Cre/+);Apc(15lox/15lox) mouse model. Loss of APC function in mesenchymal cells surrounding the fetal Müllerian ducts results in severe defects in the myometrial layers of the uterus in adult mice, suggesting that the WNT signaling pathway plays important roles in maintaining myometrial integrity.
    Full-text · Article · Jun 2011 · Molecular and Cellular Endocrinology
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