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Expression Profiling of Nuclear Receptors Identifies Key Roles of NR4A Subfamily in Uterine Fibroids
Open accessAbstract
Uterine fibroids (UFs), also known as uterine leiomyomas, are benign, fibrotic smooth muscle tumors. Although the GnRH analog leuprolide acetate that suppresses gonadal steroid hormones is used as a treatment, it has significant side effects, thereby limiting its use. Availability of more effective therapy is limited because of a lack of understanding of molecular underpinnings of the disease. Although ovarian steroid hormones estrogen and progesterone and their receptors are clearly involved, the role of other nuclear receptors (NRs) in UFs is not well defined. We used quantitative real-time PCR to systematically profile the expression of 48 NRs and identified several NRs that were aberrantly expressed in UFs. Among others, expression of NR4A subfamily members including NGFIB (NR4A1), NURR1 (NR4A2), and NOR1 (NR4A3) were dramatically suppressed in leiomyoma compared with the matched myometrium. Restoration of expression of each of these NR4A members in the primary leiomyoma smooth muscle cells decreased cell proliferation. Importantly, NR4As regulate expressions of the profibrotic factors including TGFβ3 and SMAD3, and several collagens that are key components of the extracellular matrix. Finally, we identify NR4A members as targets of leuprolide acetate treatment. Together, our results implicate several NRs including the NR4A subfamily in leiomyoma etiology and identify NR4As as potential therapeutic targets for treating fibrotic diseases.
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Metadata
- Authors
- Yin, H., Lo, J. H., Kim, J.-Y., Marsh, E. E., Kim, J. J., Ghosh, A. K., Bulun, S., & Chakravarti, D.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Chakravarti, Debabrata
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2013-05-01
- Volume
- 27
- Issue
- 5
- Pages
- 726-740
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC3634117
- OpenAlex
- W2053265138
- Cited by
- 31
- References
- 61
- Citations by year
- 2025: 2 · 2024: 2 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 6 · 2014: 3
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Northwestern University
- National Institutes of Health
- University of California, Los Angeles
- Feinberg School of Medicine
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD057877)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- uterine fibroids, leiomyoma, nuclear receptors, Nurr1, NOR-1, leuprolide, smooth muscle cell proliferation, TGF-beta3, Smad3, collagen expression, extracellular matrix, fibrosis, therapeutic target
- MeSH terms
- Adult, Binding Sites, Female, Humans, Leiomyoma, Middle Aged, Models, Biological, Myometrium, Protein Binding, Uterine Neoplasms, Gene Expression Regulation, Neoplastic, Leuprolide, Response Elements, Gene Expression Profiling, Myocytes, Smooth Muscle, Cell Proliferation, Orphan Nuclear Receptors
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