Although the uterus is indispensable for propagation, and thus survival, of mammalian species, its differentiation from the primordial Mullerian ducts is not well understood. We hypothesize that 2-catenin plays a major role in postnatal uterine development and that its dysregulated function may be an underlying cause of leiomyomata, the most common gynecologic tumor. Conventional Wnt- mediated signal transduction occurs by the stabilization of 2-catenin and its translocation to the nucleus and interaction with the transcription factors TCF/LEF to modulate target gene expression. Additionally, 2-catenin plays an essential role in linking adherens junctions with the actin cytoskeleton. We are investigating the function of 2-catenin in uterine development and have found that targeted deletion of 2-catenin in mouse uterus leads to progressive replacement of smooth muscle with fat in the myometrium with estrous cycling. These results suggested that there is a regenerative cell in the uterus that is dependent on 2-catenin function and is hormonally regulated. We propose to continue these studies by- (I) Identifying the uterine smooth muscle cells that behave like the regenerative satellite cells in skeletal muscle. (II) Determining the source of the cells that contribute to uterine smooth muscle. (III) Determining whether the muscle-fat phenotype is due to the adhesion or the nuclear function of 2-catenin. The results of these studies will provide a better understanding of postnatal uterine development and should provide clues to the etiology of uterine muscle pathologies such a leiomyomata, which are more commonly known as uterine fibroids. More knowledge is needed about the process of uterine development and function, particularly when these processes are perturbed as with uterine fibroids, a significant indicator for hysterectomy. Understanding the mechanisms governing development of these benign tumors in the uterus should lead to safe, long-term medical therapies based on scientific rationales that could benefit thousands of women annually who might be spared surgery.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD052701-05
Application #
8207830
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Parrott, Estella C
Project Start
2008-03-02
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$303,971
Indirect Cost
$120,371
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Tanwar, Pradeep S; Kaneko-Tarui, Tomoko; Lee, Ho-Joon et al. (2013) PTEN loss and HOXA10 expression are associated with ovarian endometrioid adenocarcinoma differentiation and progression. Carcinogenesis 34:893-901
Tanaka, Yoshihiro; Park, Joo Hyun; Tanwar, Pradeep S et al. (2012) Deletion of tuberous sclerosis 1 in somatic cells of the murine reproductive tract causes female infertility. Endocrinology 153:404-16
Meirelles, Katia; Benedict, Leo Andrew; Dombkowski, David et al. (2012) Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Proc Natl Acad Sci U S A 109:2358-63
Tanwar, Pradeep S; Zhang, LiHua; Roberts, Drucilla J et al. (2011) Stromal deletion of the APC tumor suppressor in mice triggers development of endometrial cancer. Cancer Res 71:1584-96
Tanwar, Pradeep S; Zhang, Lihua; Teixeira, Jose M (2011) Adenomatous polyposis coli (APC) is essential for maintaining the integrity of the seminiferous epithelium. Mol Endocrinol 25:1725-39
Tanwar, Pradeep S; Zhang, LiHua; Kaneko-Tarui, Tomoko et al. (2011) Mammalian target of rapamycin is a therapeutic target for murine ovarian endometrioid adenocarcinomas with dysregulated Wnt/?-catenin and PTEN. PLoS One 6:e20715
Park, Joo Hyun; Daheron, Laurence; Kantarci, Sibel et al. (2011) Human endometrial cells express elevated levels of pluripotent factors and are more amenable to reprogramming into induced pluripotent stem cells. Endocrinology 152:1080-9
Tanwar, Pradeep S; Kaneko-Tarui, Tomoko; Zhang, LiHua et al. (2010) Constitutive WNT/beta-catenin signaling in murine Sertoli cells disrupts their differentiation and ability to support spermatogenesis. Biol Reprod 82:422-32
Papakostas, Thanos D; Pieretti-Vanmarcke, Rafael; Nicolaou, Fotini et al. (2010) Development of an efficiently cleaved, bioactive, highly pure FLAG-tagged recombinant human Mullerian Inhibiting Substance. Protein Expr Purif 70:32-8
Tanwar, Pradeep S; Zhang, LiHua; Tanaka, Yoshihiro et al. (2010) Focal Mullerian duct retention in male mice with constitutively activated beta-catenin expression in the Mullerian duct mesenchyme. Proc Natl Acad Sci U S A 107:16142-7

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