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: 3.45). 05/2009; 81(3):545-52. DOI: 10.1095/biolreprod.108.075648
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    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.
    Molecular and Cellular Endocrinology 06/2011; 341(1-2):48-54. DOI:10.1016/j.mce.2011.05.026 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review highlights the current techniques used to generate transgenic mouse models of cancer, with an emphasis on recent advances in the use of ubiquitous promoters, models that use Cre-loxP and Flip-FRT recombinase technology, inducible systems, RNAi to target genes, and transposon mutagenesis. A concluding section discusses new imaging systems that visualize tumor progression and the microenvironment in vivo. In this review, these techniques and strategies used in mouse models of cancer are highlighted, as they are pertinent and relevant to the development of zebrafish models of cancer.
    Zebrafish 12/2009; 6(4):329-37. DOI:10.1089/zeb.2009.0626 · 1.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Uterine tumors, whether benign or malignant, are diagnosed in a significant portion of women and are associated with a number of co-morbidities that negatively impact quality of life. Uterine tumors can be derived from the epithelial (endometrial hyperplasia or carcinoma) and mesenchymal (leiomyoma, sarcoma) layers of the uterus. The exact etiologies of the various tumor types are yet to be defined. Collectively their development and progression often results from aberrant steroid hormone exposure or dysregulation of related growth factor signaling and apoptotic pathways, reflecting the role of steroid hormone-dependent signaling and survival pathways in the cycles of cell growth and involution that characterize normal uterine physiology. While molecular analyses of human tumors can identify candidate genetic and epigenetic lesions contributing to uterine tumor initiation and progression, in vivo genetic models are needed to establish the functional significance of such lesions and their contribution to tumorigenesis. For this purpose, genetically-engineered mouse models have proven valuable. Here we review genetically-modified mouse models that develop uterine tumors and compare their pathology, utility/feasibility, and discuss their clinical relevance.
    Frontiers in bioscience (Elite edition) 01/2010; 2:882-905. DOI:10.2741/E149


Available from