Endocrinology of uterine fibroids

Moravek, Molly B.; Bulun, Serdar E.

doi:10.1097/gco.0000000000000185

Cited by 58 publications

(32 citation statements)

References 94 publications

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“…The underlying basis by which impaired Mediator kinase activity contributes to UF pathogenesis is presently unclear, but likely involves dysregulation of signal-dependent gene expression programs that control myometrial stem cell fate. In this regard, the prevailing model for UF pathogenesis invokes the genetic transformation of a single myometrial stem cell into a tumor-initiating cell (UF stem cell) that seeds and sustains clonal tumor growth, characterized by cell proliferation and abundant extracellular matrix production, under the influence of endocrine, autocrine, and paracrine growth factor and hormone receptor signaling (47). Given the critical role of the Mediator kinase module as an integrative hub for cell signaling in the nucleus, disruption of Mediator kinase activity through oncogenic mutations in MED12 could thus trigger widespread transcriptional reprogramming that drives myometrial stem cell transformation.…”

Section: Oncogenic Med12 Mutations Disrupt Cdk8/19 Activitymentioning

confidence: 99%

Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19

Park¹,

Shen²,

Spaeth³

et al. 2018

Journal of Biological Chemistry

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Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12-dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs.

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Section: Oncogenic Med12 Mutations Disrupt Cdk8/19 Activitymentioning

confidence: 99%

Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19

Park¹,

Shen²,

Spaeth³

et al. 2018

Journal of Biological Chemistry

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“…Progesterone has recently become a focus of research in UL development and growth [51], and may be the primary hormone stimulating UL growth [52, 53]. In in vivo models, progesterone and the progesterone receptor directly induced growth, likely through the production of extracellular matrix via down-regulation of a tumor suppressor [53–55].…”

Section: Etiologic Hypotheses and Risk Factorsmentioning

confidence: 99%

Epidemiology of Uterine Fibroids

Wise

Laughlin-Tommaso

2016

Clinical Obstetrics &Amp; Gynecology

269

122

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Uterine leiomyomata (UL) have a substantial impact on women's health, but relatively few studies have identified opportunities for primary prevention of these neoplasms. Most established risk factors are not modifiable, including premenopausal age, African ancestry, age at menarche, and childbearing history. The main challenge in studying UL is that a large proportion of tumors are asymptomatic. Herein, we review the epidemiology of UL from published studies to date. We highlight the advantages of ultrasound screening studies and the ways in which their innovative methods have helped clarify the etiology of disease. We conclude with a discussion of promising new hypotheses.

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“…Recently, there has been a shift of focus to not only include steroid hormones but to explore the role of genetics and stem cells in fibroid development and growth (Moravek and Bulun, 2015). Genetic abnormalities, recurrent genetic aberrations, and mutations may also contribute to the development of uterine leiomyomas (Hodge et al , 2009, Makinen et al , 2011, Parker, 2007, Velagaleti et al , 2010) and are considered to play pivotal roles in tumorigenesis.…”

Section: Resultsmentioning

confidence: 99%

Immunoexpression of Steroid Hormone Receptors and Proliferation Markers in Uterine Leiomyoma and Normal Myometrial Tissues from the Miniature Pig, Sus scrofa

Mozzachio¹,

Moore

Kissling

et al. 2015

Toxicol Pathol

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Uterine leiomyomas in miniature pet pigs occur similarly to that in women with regards to frequency, age, parity and cycling. Clinical signs, gross and histologic features of the porcine tumors closely resemble uterine leiomyomas (fibroids) in women. Although fibroids are hormonally responsive in women, the role of estrogen and progesterone has not been elucidated. Current animal models present challenges in data extrapolation to humans. In this study, immunohistochemistry was used to assess the expression of the steroid hormone receptors, ER-α, ER-β and PR, and cell proliferation markers, PCNA and Ki-67, in tumor and matched myometrial tissues sampled from miniature pigs. A “quickscore” method was used to determine receptor expression, and percent labeling indices were calculated for the markers. ER-α/β and PR were localized to nuclei of smooth muscle cells in both tissues. PR expression was intense and diffuse throughout all tissues, with correlation between tumors and matched myometria. Conversely, ER-α expression was more variable between the tissues and animals. ER-β expression was low. PCNA and Ki-67 were localized to the nucleus and expression varied among tumors; however, normal tissues were overall negative. These findings support further investigation into the use of the miniature pig as a model of fibroids in women.

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Endocrinology of uterine fibroids

Cited by 58 publications

References 94 publications

Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19

Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19

Epidemiology of Uterine Fibroids

Immunoexpression of Steroid Hormone Receptors and Proliferation Markers in Uterine Leiomyoma and Normal Myometrial Tissues from the Miniature Pig, Sus scrofa

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