title: Expression profiling of nuclear receptors identifies key roles of NR4A subfamily in uterine fibroids.
abstract: 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.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Hanwei
authors.initials: H
authors.lastname: Yin
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lo
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Erica E
authors.initials: EE
authors.lastname: Marsh
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Serdar
authors.initials: S
authors.lastname: Bulun
authors.forename: Debabrata
authors.initials: D
authors.lastname: Chakravarti
mesh_terms: D000328:Adult; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007889:Leiomyoma / Q000235:genetics*; D016729:Leuprolide / Q000494:pharmacology; D008875:Middle Aged; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020218:Response Elements / Q000235:genetics; D014594:Uterine Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: D057093:Orphan Nuclear Receptors; D016729:Leuprolide
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