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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057877-05
Application #
8495371
Study Section
Special Emphasis Panel (ZHD1-DSR-K (BS))
Program Officer
Parrott, Estella C
Project Start
2009-08-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$1,042,031
Indirect Cost
$270,439
Name
Northwestern University at Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Sengoba, Katherine S; Ghant, Marissa S; Okeigwe, Ijeoma et al. (2017) Racial/Ethnic Differences in Women's Experiences with Symptomatic Uterine Fibroids: a Qualitative Assessment. J Racial Ethn Health Disparities 4:178-183
Zhang, Qing; Poropatich, Kate; Ubago, Julianne et al. (2017) Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei. Int J Gynecol Pathol :
Marsh, Erica E; Bernardi, Lia A; Steinberg, Marissa L et al. (2016) Novel correlates between antimüllerian hormone and menstrual cycle characteristics in African-American women (23-35 years-old). Fertil Steril 106:443-450.e2
Ubago, Julianne M; Zhang, Qing; Kim, Julie J et al. (2016) Two Subtypes of Atypical Leiomyoma: Clinical, Histologic, and Molecular Analysis. Am J Surg Pathol 40:923-33
Marsh, Erica E; Steinberg, Marissa L; Parker, J Brandon et al. (2016) Decreased expression of microRNA-29 family in leiomyoma contributes to increased major fibrillar collagen production. Fertil Steril 106:766-72
Koohestani, Faezeh; Qiang, Wenan; MacNeill, Amy L et al. (2016) Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model. Hum Reprod 31:1540-51
Marsh, Erica E; Chibber, Shani; Wu, Ju et al. (2016) Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 expression and regulation in uterine leiomyoma. Fertil Steril 105:1070-5
Vidimar, Vania; Gius, David; Chakravarti, Debabrata et al. (2016) Dysfunctional MnSOD leads to redox dysregulation and activation of prosurvival AKT signaling in uterine leiomyomas. Sci Adv 2:e1601132
Yin, Ping; Ono, Masanori; Moravek, Molly B et al. (2015) Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo. J Clin Endocrinol Metab 100:E601-6

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