Dataset Information

Impact of Genetic Variants in Estrogen Receptor-? Gene in the Etiology of Uterine Leiomyomas.

ABSTRACT: Background:Uterine leiomyomas are steroid hormone dependent myometrial neoplasms of female genital tract which appear after menarche and regress at menopause. The present study evaluated the role of ER-? gene polymorphisms (rs3020449 C/T, rs3020450 G/A, rs1271572 G/T, rs1256049 G/Aand rs4986938 G/A) in the etiology of disease. Methods:A total of 150 clinically, ultrasonographically evaluated uterine leiomyoma patients and an equal number of individuals as controls were considered for the present study. Genotype analysis was carried out by TETRA Primer Amplification Refractory Mutation System-PCR for promoter polymorphisms and PCR- RFLP method was done for exonic polymorphisms followed by agarose gel electrophoresis. The strength of the association of ER-? gene polymorphisms between controls and patients were measured by appropriate statistical methods. Results:An increased frequency of T/T genotype and T allele of rs3020449, AA genotype and A allele of rs3020450, T/T genotype and T allele of rs1271572, AA genotype and A allele of rs1256049 and A/A genotype and A allele of rs4986938 was observed in cases when compared with controls. Conclusion:The study indicates that the ER-? gene polymorphisms may act as a major genetic regulator in the etiology of uterine leiomyomas.

SUBMITTER: Bharathi C

PROVIDER: S-EPMC6670268 | biostudies-literature | 2019 Jul-Sep

REPOSITORIES: biostudies-literature

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Impact of Genetic Variants in Estrogen Receptor-β Gene in the Etiology of Uterine Leiomyomas.

Bharathi Chitroju C Anupama Desamala D Pratibha Nallari N Venkateshwari Anantapur A

Journal of reproduction & infertility 20190701 3

<h4>Background</h4>Uterine leiomyomas are steroid hormone dependent myometrial neoplasms of female genital tract which appear after menarche and regress at menopause. The present study evaluated the role of ER-β gene polymorphisms (rs3020449 C/T, rs3020450 G/A, rs1271572 G/T, rs1256049 G/Aand rs4986938 G/A) in the etiology of disease.<h4>Methods</h4>A total of 150 clinically, ultrasonographically evaluated uterine leiomyoma patients and an equal number of individuals as controls were considered ...[more]

PMID: 31423418

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Project description:The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-β-dependent transcription in a pregnancy-specific endothelium-dependent manner. Plasma estradiol levels increased and peaked in late pregnancy and returned to prepregnant levels post-partum, correlating with uterine artery AT2R and ERβ upregulation. Estradiol stimulated AT2R mRNA expression in endothelium-intact but not endothelium-denuded late pregnant and nonpregnant rat uterine artery ex vivo. Consistently, estradiol stimulated AT2R mRNA expression in late pregnant but not nonpregnant primary human uterine artery endothelial cells in vitro, which was abolished by ER antagonist ICI 182,780. Higher ERα protein bound to ER-responsive elements in AT2R promoter in the nonpregnant arteries whereas higher ERβ bound in the pregnant state. ERα protein levels were similar but higher ERβ protein levels were expressed in pregnant versus nonpregnant human uterine artery endothelial cells. Estradiol stimulation recruited ERα to the AT2R promoter in the nonpregnant state and ERβ to the AT2R promoter in pregnancy; however, only ERβ recruitment mediated transactivation of the AT2R reporter gene in pregnant human uterine artery endothelial cells. Estradiol-induced AT2R expression was abolished by the specific ERβ (not ERα) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) and mimicked by the specific ERβ (not ERα) agonist 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) in pregnant human uterine artery endothelial cells in vitro. This study demonstrates a novel role of pregnancy-augmented ERβ in AT2R upregulation in the uterine artery and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.

Project description:Loss-of-function germline mutations in the fumarase (FH) gene of the Krebs cycle characterize hereditary leiomyomatosis and renal cell cancer syndrome. Fumarase (FH) deficiency can be diagnosed by the loss of immunohistochemical expression. In this study, we investigated the occurrence and clinicopathologic features of FH-deficient uterine smooth muscle tumors (SMTs). A total of 1583 uterine and 157 nonuterine SMTs were examined using a polyclonal FH antibody and automated immunohistochemistry, and 86 uterine leiomyomas with an FH loss were identified. The frequencies of FH deficiency for subcohorts of uterine SMTs were 1.6% for unselected nonatypical leiomyomas, 1.8% for cellular leiomyomas, 37.3% for atypical leiomyomas, and 0% for leiomyosarcomas. One extrauterine, retroperitoneal estrogen receptor-positive leiomyoma was also FH deficient. The patient age of FH-deficient uterine leiomyomas was 20 to 52 years (median, 38 y). Grossly, these tumors were often soft and amorphous resembling a fibrothecoma. Histologically, the FH-deficient nonatypical leiomyomas lacked cellular packeting and distinct collagenous zones and showed chain-like or palisading nuclear arrangements, prominent staghorn-shaped blood vessels, oval nuclei with no or at most mild atypia, small eosinophilic nucleoli, and a low mitotic rate (0 to 1/10 HPF). The FH-deficient atypical leiomyomas had nuclear atypia often manifesting as multinucleation, prominent eosinophilic nucleoli, and mitotic activity up to 7/10 HPF, with atypical mitoses seen in 32% of cases. However, similar histologic changes were seen in some non-FH-deficient atypical leiomyomas. Loss-of-function FH-gene mutations including 5 whole-gene deletions and 3 frameshift mutations were identified in 8 of 16 FH-deficient nonatypical leiomyomas using multiplex ligation-dependent probe amplification and Sanger sequencing, respectively. Follow-up data on patients with FH-deficient atypical uterine leiomyomas revealed 19 patients alive (median follow-up 27 y) and 5 patients dead. Deaths occurred 9 to 30 years after surgery at a median age of 72 years; causes of death could not be determined. These results indicate that FH-deficient uterine leiomyomas occur with a high frequency among atypical leiomyomas and infrequently in nonatypical leiomyomas and are often histologically distinctive. They seem to have a low biological potential and lack any significant association with leiomyosarcoma.

Dataset Information

Impact of Genetic Variants in Estrogen Receptor-? Gene in the Etiology of Uterine Leiomyomas.

Publications

Impact of Genetic Variants in Estrogen Receptor-β Gene in the Etiology of Uterine Leiomyomas.

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