Uterine leiomyomata (fibroids) represent the most prevalent benign gynecologic disorder in the US. The cellular and molecular mechanisms regulating the development and growth of leiomyoma are not well understood. Our multidisciplinary team has designed 3 well-integrated projects focusing on Interactions between biologically critical hormonal pathways in uterine leiomyoma involving the transcription factors progesterone receptor (PR) and FOXO, the signaling pathway PI3K/AKT and the pro-fibrotic factor TGF-beta. Project I (Bulun) will be pursued to understand the mechanisms as to how antl-progestins such as RU486 reduce tumor size. We hypothesize that progesterone regulates a number of critical genes, that favors increased proliferation and decreased apoptosis of leiomyoma smooth muscle cells, whereas anti-progestins reverse this effect by enhancing apoptosis and decreasing proliferation. Project II (Kim/Chakravarti) will determine the role of the PI3K/AKT/F0X0 signaling pathway regulating leiomyoma cell growth and survival in response to progesterone. We hypothesize that progesterone Induces proliferation of leiomyoma cells through activation of the PI3K/AKT/F0X0 signaling pathway and that Inhibitors of the AKT pathway should override the proliferative effects of progesterone and promote apoptosis. Project III (Nowak) will define the mechanisms as to how antifibrotic drugs regulate leiomyoma growth. We hypothesize that the Increased proliferation exhibited by leiomyoma smooth muscle cells Is due to a major shift in the extracellular matrix environment caused by increased synthesis of new, monomeric collagen type I by these cells. We will determine whether antifibrotic drugs may be an effective new treatment for leiomyomas. These projects are supported by an Administrative Core (Bulun) and Tissue Procurement and Cell Culture Core (Kurita). Overall, as part of our long range goal, all projects investigate local hormonal signaling regulating apoptosis and proliferation as biologic endpoints and test existing and upcoming pharmaceutical compounds that target these pathways in uterine leiomyomata.

Public Health Relevance

Symptomatic uterine leiomyomata affect millions of US women and cause irregular uterine bleeding, anemia, recurrent pregnancy loss leading to more than 200,000 hysterectomies per year. Available treatments are limited due in large part to the fact that the mechanisms regulating the development and growth of these tumors are unclear. We propose integrated molecular, cellular and translational studies that should lead to a better understanding and future development of novel therapeutics for uterine leiomyomata.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-K (BS))
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Parrott, Estella C
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Northwestern University at Chicago
Obstetrics & Gynecology
Schools of Medicine
United States
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Kim, Ji-Young; Banerjee, Taraswi; Vinckevicius, Aurimas et al. (2014) A role for WDR5 in integrating threonine 11 phosphorylation to lysine 4 methylation on histone H3 during androgen signaling and in prostate cancer. Mol Cell 54:613-25
Marsh, Erica E; Brocks, Maureen E; Ghant, Marissa S et al. (2014) Prevalence and knowledge of heavy menstrual bleeding among African American women. Int J Gynaecol Obstet 125:56-9
Ono, Masanori; Yin, Ping; Navarro, Antonia et al. (2014) Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth. Fertil Steril 101:1441-9
Xu, Xiaofei; Lu, Zhenxiao; Qiang, Wenan et al. (2014) Inactivation of AKT induces cellular senescence in uterine leiomyoma. Endocrinology 155:1510-9
Navarro, Antonia; Yin, Ping; Ono, Masanori et al. (2014) 5-Hydroxymethylcytosine promotes proliferation of human uterine leiomyoma: a biological link to a new epigenetic modification in benign tumors. J Clin Endocrinol Metab 99:E2437-45
Yin, Hanwei; Lo, Jay H; Kim, Ji-Young et al. (2013) Expression profiling of nuclear receptors identifies key roles of NR4A subfamily in uterine fibroids. Mol Endocrinol 27:726-40
Marsh, Erica E; Ekpo, Geraldine E; Cardozo, Eden R et al. (2013) Racial differences in fibroid prevalence and ultrasound findings in asymptomatic young women (18-30ýýyears old): a pilot study. Fertil Steril 99:1951-7
Sefton, Elizabeth C; Qiang, Wenan; Serna, Vanida et al. (2013) MK-2206, an AKT inhibitor, promotes caspase-independent cell death and inhibits leiomyoma growth. Endocrinology 154:4046-57
Varghese, Binny V; Koohestani, Faezeh; McWilliams, Michelle et al. (2013) Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway. Proc Natl Acad Sci U S A 110:2187-92
Ono, Masanori; Yin, Ping; Navarro, Antonia et al. (2013) Paracrine activation of WNT/*-catenin pathway in uterine leiomyoma stem cells promotes tumor growth. Proc Natl Acad Sci U S A 110:17053-8

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