Uterine leiomyomas (fibroids) represent the most common tumor in women, disproportionately affect African- Americans, cause pregnancy loss, and induce excessive uterine bleeding leading to severe chronic anemia. Our long-term objective is to understand novel clinically relevant mechanisms responsible for the pathogenesis and growth of uterine leiomyomas in order to reduce associated morbidity. Our team has designed integrated projects focusing on paracrine interactions among leiomyoma cell populations and biologically critical signaling pathways involving RANKL/RANK, NR4A subfamily of nuclear receptors and AKT. Project I (Bulun) seeks to understand the mechanisms responsible for clonal expansion of a small but distinct stem cell population deficient in estrogen or progesterone receptors. Progesterone action, essential for the in vivo growth of leiomyomas, are transduced from steroid receptor-rich and mature leiomyoma cells onto the stem/progenitor cells via a paracrine signaling pathway involving the cytokine RANKL secreted by support cells for activating its receptor RANK in stem cells, triggering self-renewal and proliferation. Targetin RANK pathway in a unique stem cell population, responsible for regeneration and proliferation of leiomyomas, is a novel and clinically significant approach. Project II (Chakravarti/Nowak) was launched after system-wide expression profiling of the entire nuclear receptor family, which showed severe deficiencies of the NR4A subfamily expression in uterine leiomyomas. Project II will test the hypothesis that the NR4A members play critical and integrative roles involving TGF?3 and SMAD signaling in leiomyoma growth by regulating key proliferation and profibrotic genes. Elucidation of a novel role of a nuclear receptor subfamily deficiency in the context of proliferation and fibrosis is novel and a paradigm shift for identifying therapeutic targets. Projet III (Kim/Wei) will define the mechanisms that promote cellular senescence and death upon inhibition of AKT, which mediates the major signaling pathway for leiomyoma cell survival. Project III will test the hypothesis that the high oxidative stress levels in leiomyomas is able to promote growth and survival through the AKT pathway, however, upon inhibition of AKT, reactive oxygen species will induce miR-182, p16 and HMGA2 and cause senescence. AKT inhibition will also decrease BCL2 and enhances cell death. Pursuing AKT-dependent senescence and death pathways through ROS in uterine leiomyoma cells is both novel and translational. Optimally organized Administrative (Bulun) and Tissue/Cell (Wei/Marsh) Cores run by experienced Directors support these projects. Overall, all projects are clinically and thematically connected, collectively investigate self-renewal, proliferation, senescence and cell death in stem and differentiated cell populations of uterine fibroids, and are designed to introduce paradigm-shifting pathologic and therapeutic concepts. Just as the past funding period of this P01 Center led to the use of antiprogestins to treat uterine leiomyomas, we expect the development of novel treatments targeting RANKL/RANK, NR4A or AKT as a result of the proposed studies.

Public Health Relevance

Symptomatic uterine leiomyomas affect millions of US women and cause recurrent pregnancy loss, excessive and irregular uterine bleeding, and severe anemia leading to more than 200,000 hysterectomies per year. Available treatments are limited due in large to the fact that the mechanisms regulating tumor initiation and further growth are unclear. We propose integrated cellular, molecular, and paradigm-shifting studies that will lead to better understanding and future development of novel therapeutics for uterine leimoyomas.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057877-09
Application #
9550845
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Tingen, Candace M
Project Start
2008-04-01
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Griffin, Brannan B; Ban, Yanli; Lu, Xinyan et al. (2018) Hydropic leiomyoma: a distinct variant of leiomyoma closely related to HMGA2 overexpression. Hum Pathol :
Xu, Xiuhua; Kim, J Julie; Li, Yinuo et al. (2018) Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma. J Mol Med (Berl) 96:1095-1106
Zhang, Qing; Kanis, Margaux Jenna; Ubago, Julianne et al. (2018) The selected biomarker analysis in 5 types of uterine smooth muscle tumors. Hum Pathol 76:17-27
Zhang, Qing; Poropatich, Kate; Ubago, Julianne et al. (2018) Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei. Int J Gynecol Pathol 37:421-430
Ikhena, Deborah E; Liu, Shimeng; Kujawa, Stacy et al. (2018) RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth. J Clin Endocrinol Metab 103:1842-1849
Ikhena, Deborah E; Bulun, Serdar E (2018) Literature Review on the Role of Uterine Fibroids in Endometrial Function. Reprod Sci 25:635-643
Vidimar, Vania; Chakravarti, Debabrata; Bulun, Serdar E et al. (2018) The AKT/BCL-2 Axis Mediates Survival of Uterine Leiomyoma in a Novel 3D Spheroid Model. Endocrinology 159:1453-1462
Xie, Jia; Xu, Xiuhua; Yin, Ping et al. (2018) Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma. Lab Invest 98:1575-1587
Xie, Jia; Ubango, Julianne; Ban, Yanli et al. (2018) Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations. Genes Chromosomes Cancer 57:485-494
Park, Min Ju; Shen, Hailian; Spaeth, Jason M et al. (2018) Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. J Biol Chem 293:4870-4882

Showing the most recent 10 out of 54 publications