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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Parrott, Estella C
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Massachusetts General Hospital
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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
Tanwar, Pradeep S; Kaneko-Tarui, Tomoko; Zhang, LiHua et al. (2012) Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis. Hum Mol Genet 21:4394-405
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; Kaneko-Tarui, Tomoko; Zhang, Lihua et al. (2012) Stromal liver kinase B1 [STK11] signaling loss induces oviductal adenomas and endometrial cancer by activating mammalian Target of Rapamycin Complex 1. PLoS Genet 8:e1002906
Tanwar, Pradeep S; Commandeur, Arno E; Zhang, LiHua et al. (2012) The Mullerian inhibiting substance type 2 receptor suppresses tumorigenesis in testes with sustained ýý-catenin signaling. Carcinogenesis 33:2351-61
Zhang, Ling; Patterson, Amanda L; Zhang, Lihua et al. (2012) Endometrial stromal beta-catenin is required for steroid-dependent mesenchymal-epithelial cross talk and decidualization. Reprod Biol Endocrinol 10:75
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

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