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Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.

ABSTRACT: Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductive-aged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase-protein kinase B/AKT-mammalian target of rapamycin (PI3K/AKT-mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K-AKT-mTOR pathways and cell proliferation specifically in cultured primary leiomyoma cells. Additionally, we report that RE1 suppressing transcription factor/neuron-restrictive silencing factor (REST/NRSF), a known tumor suppressor, transcriptionally represses GPR10 in the normal myometrium, and that the loss of REST in fibroids permits GPR10 expression. Importantly, mice overexpressing human GPR10 in the myometrium develop myometrial hyperplasia with excessive extracellular matrix deposition, a hallmark of uterine fibroids. We demonstrate previously unrecognized roles for GPR10 and its upstream regulator REST in the pathogenesis of uterine fibroids. Importantly, we report a unique genetically modified mouse model for a gene that is misexpressed in uterine fibroids.

SUBMITTER: Varghese BV

PROVIDER: S-EPMC3568308 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.

Varghese Binny V BV Koohestani Faezeh F McWilliams Michelle M Colvin Arlene A Gunewardena Sumedha S Kinsey William H WH Nowak Romana A RA Nothnick Warren B WB Chennathukuzhi Vargheese M VM

Proceedings of the National Academy of Sciences of the United States of America 20130102 6

Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductive-aged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase-protein kinase B/AKT ...[more]

PMID: 23284171

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Project description:BackgroundUterine fibroids are the most common benign uterine tumours present in women of reproductive age. Mifepristone (RU-486) competitively binds and inhibits progesterone receptors. Studies have suggested that fibroid growth depends on the sexual steroids. Mifepristone has been shown to decrease fibroid size. This review summarises the effects of mifepristone treatment on fibroids and the associated adverse effects as described in randomised controlled trials.ObjectivesTo determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women.Search methodsWe searched the specialised register of the Cochrane Menstrual Disorders and Subfertility (Cochrane Menstrual Disorders and subfertility Review Group), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE, EMBASE, PsycINFO, and CINAHL (to November 2011). We handsearched a number of journals, and searched reference lists, databases of ongoing trials and the Internet. There were no language restrictions.Selection criteriaOnly truly randomised controlled trials of mifepristone versus other forms of medical therapy or placebo in pre-menopausal women with confirmed uterine fibroids were included.Data collection and analysisFour authors independently extracted data and assessed trial quality. Data were analysed using the Peto odds ratios (OR) for dichotomous data and the weighted mean differences for continuous data, with 95% confidence intervals (CI). Meta-analyses were performed using the fixed-effect model.Main resultsThree studies involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placebo and vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo (Peto OR 17.84; 95% CI 6.72 to 47.38; 2 RCTs, 77 women, I(2) = 0%). Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on the fibroid volume (standardised mean difference (SMD) -0.02; 95% CI -0.38 to 0.41; 99 women). Two studies (Bagaria 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on uterine volume (mean difference (MD) -77.24; 95% CI -240.62 to 86.14; 72 women). The pooled data suggest an increased adverse event (abnormal endometrial histology) in the mifepristone group compared to placebo (OR 31.65; 95% CI 4.83 to 207.35; 2 RCTs; 54 women; I(2) = 0%). Only one study (Bagaria 2009) reported endometrial hyperplasia at the end of the therapy (12/19 women in the mifepristone group versus 0/16 in the placebo group; OR 55.0; 95% CI 2.86 to 105.67). Engman 2009 found a significantly higher rate of cystic glandular dilatation in women in the mifepristone group (5/8 women biopsied) compared with the placebo group (1/11 women biopsied) (OR 16.67; 95% CI 1.36 to 204.03). One study (Fiscella 2006) suggested significant improvements (P < 0.001) for specific quality of life outcomes.Authors' conclusionsMifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use of mifepristone for the treatment of uterine fibroids.

Project description:BackgroundUterine fibroids are the most common non-malignant growths in women of childbearing age. They are associated with heavy menstrual bleeding and subfertility. Herbal preparations are commonly used as alternatives to surgical procedures.ObjectivesTo assess the benefits and risks of herbal preparations for uterine fibroids.Search strategyAuthors searched following electronic databases: the Trials Registers of the Cochrane Menstrual Disorders and Subfertility Group and the Cochrane Complementary Medicine Field, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, the Chinese Biomedical Database, the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), AMED, and LILACS. The searches ended on 31st December 2008.Selection criteriaRandomised controlled trials comparing herbal preparations with no intervention, placebo, medical treatment or surgical procedures in women with uterine fibroids. We also included trials of herbal preparations with or without conventional therapy.Data collection and analysisTwo review authors collected data independently. We assessed trial risk of bias according to our methodological criteria . We presented dichotomous data as risk ratios (RR) and continuous outcomes as mean difference (MD), both with 95% confidence intervals (CI).Main resultsWe included two randomised trials (involved 150 women) with clear description of randomisation methods. The methodological risk of bias of the trials varied. There were variations in the tested herbal preparations, and the treatment duration was six months. The outcomes available were not the primary outcomes selected for this review, such as symptom relief or the need for surgical treatment; trials mainly reported outcomes in terms of shrinkage of the fibroids.Compared with mifepristone, Huoxue Sanjie decoction showed no significant difference in the disappearance of uterine fibroids, number of patients with shrinking of uterine fibroids or average volume of uterine fibroids, but less effective than mifepristone on reducing average size of uterus (mean difference 23.23 cm(3),95% confidence interval 17.85 to 28.61). There was no significant difference between Nona Roguy herbal product and GnRH agonist in average volume of uterine fibroids or size of uterus. No serious adverse effects from herbal preparations was reported.Authors' conclusionsCurrent evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies of large sample and high quality. Further high quality trials evaluating clinically relevant outcomes are warranted.

Dataset Information

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.

Publications

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.

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