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Cheng YH, Huang CW, Lien HT, Hsiao YY, Weng PL, Chang YC, Cheng JH, Lan KC. A Preliminary Investigation of the Roles of Endometrial Cells in Endometriosis Development via In Vitro and In Vivo Analyses. Int J Mol Sci 2024; 25:3873. [PMID: 38612685 PMCID: PMC11011664 DOI: 10.3390/ijms25073873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/24/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Endometriosis is a complex gynecological disease that affects more than 10% of women in their reproductive years. While surgery can provide temporary relief from women's pain, symptoms often return in as many as 75% of cases within two years. Previous literature has contributed to theories about the development of endometriosis; however, the exact pathogenesis and etiology remain elusive. We conducted a preliminary investigation into the influence of primary endometrial cells (ECs) on the development and progression of endometriosis. In vitro studies, they were involved in inducing Lipopolysaccharide (LPS) in rat-isolated primary endometrial cells, which resulted in increased nuclear factor-kappa B (NF-κB) and vascular endothelial growth factor (VEGF) mRNA gene expression (quantitative polymerase chain reaction analysis, qPCR) and protein expression (western blot analysis). Additionally, in vivo studies utilized autogenic and allogeneic transplantations (rat to rat) to investigate endometriosis-like lesion cyst size, body weight, protein levels (immunohistochemistry), and mRNA gene expression. These studies demonstrated that estrogen upregulates the gene and protein regulation of cytoskeletal (CK)-18, transforming growth factor-β (TGF-β), VEGF, and tumor necrosis factor (TNF)-α, particularly in the peritoneum. These findings may influence cell proliferation, angiogenesis, fibrosis, and inflammation markers. Consequently, this could exacerbate the occurrence and progression of endometriosis.
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Affiliation(s)
- Yin-Hua Cheng
- Department of Medical Research and Development, Jen-Ai Hospital, Taichung 412, Taiwan;
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (H.-T.L.); (Y.-Y.H.); (P.-L.W.); (Y.-C.C.)
| | - Ching-Wei Huang
- Division of Urology, Department of Surgery, Jen-Ai Hospital, Taichung 412, Taiwan;
| | - Hao-Ting Lien
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (H.-T.L.); (Y.-Y.H.); (P.-L.W.); (Y.-C.C.)
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College, Kaohsiung 833, Taiwan
| | - Yu-Yang Hsiao
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (H.-T.L.); (Y.-Y.H.); (P.-L.W.); (Y.-C.C.)
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College, Kaohsiung 833, Taiwan
| | - Pei-Ling Weng
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (H.-T.L.); (Y.-Y.H.); (P.-L.W.); (Y.-C.C.)
| | - Yung-Chiao Chang
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (H.-T.L.); (Y.-Y.H.); (P.-L.W.); (Y.-C.C.)
| | - Jai-Hong Cheng
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
- Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Department of Leisure and Sports Management, Cheng Shiu University, Kaohsiung 833, Taiwan
| | - Kuo-Chung Lan
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan; (H.-T.L.); (Y.-Y.H.); (P.-L.W.); (Y.-C.C.)
- Department of Obstetrics and Gynecology, Jen-Ai Hospital, Taichung 412, Taiwan
- Center for Menopause and Reproductive Medicine Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
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Yu K, Huang ZY, Xu XL, Li J, Fu XW, Deng SL. Estrogen Receptor Function: Impact on the Human Endometrium. Front Endocrinol (Lausanne) 2022; 13:827724. [PMID: 35295981 PMCID: PMC8920307 DOI: 10.3389/fendo.2022.827724] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/01/2022] [Indexed: 12/12/2022] Open
Abstract
The physiological role of estrogen in the female endometrium is well established. On the basis of responses to steroid hormones (progesterone, androgen, and estrogen), the endometrium is considered to have proliferative and secretory phases. Estrogen can act in the endometrium by interacting with estrogen receptors (ERs) to induce mucosal proliferation during the proliferative phase and progesterone receptor (PR) synthesis, which prepare the endometrium for the secretory phase. Mouse knockout studies have shown that ER expression, including ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) in the endometrium is critical for normal menstrual cycles and subsequent pregnancy. Incorrect expression of ERs can produce many diseases that can cause endometriosis, endometrial hyperplasia (EH), and endometrial cancer (EC), which affect numerous women of reproductive age. ERα promotes uterine cell proliferation and is strongly associated with an increased risk of EC, while ERβ has the opposite effects on ERα function. GPER is highly expressed in abnormal EH, but its expression in EC patients is paradoxical. Effective treatments for endometrium-related diseases depend on understanding the physiological function of ERs; however, much less is known about the signaling pathways through which ERs functions in the normal endometrium or in endometrial diseases. Given the important roles of ERs in the endometrium, we reviewed the published literature to elaborate the regulatory role of estrogen and its nuclear and membrane-associated receptors in maintaining the function of endometrium and to provide references for protecting female reproduction. Additionally, the role of drugs such as tamoxifen, raloxifene, fulvestrant and G-15 in the endometrium are also described. Future studies should focus on evaluating new therapeutic strategies that precisely target specific ERs and their related growth factor signaling pathways.
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Affiliation(s)
- Kun Yu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Zheng-Yuan Huang
- Chelsea and Westminster Hospital, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Xue-Ling Xu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Jun Li
- Department of Reproductive Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiang-Wei Fu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shou-Long Deng
- National Health Commission of China (NHC) Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
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Hirschfeld M, Ouyang YQ, Jaeger M, Erbes T, Orlowska-Volk M, Zur Hausen A, Stickeler E. HNRNP G and HTRA2-BETA1 regulate estrogen receptor alpha expression with potential impact on endometrial cancer. BMC Cancer 2015; 15:86. [PMID: 25884434 PMCID: PMC4355463 DOI: 10.1186/s12885-015-1088-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 02/19/2015] [Indexed: 01/11/2023] Open
Abstract
Background Estrogen receptor alpha (ERa/ESR1) expression is regulated by alternative splicing. Its most frequently detectable exon7 skipping isoform (ERaD7) is a dominant negative variant. Elevated expression of ERaD7 was already detected in endometrial cancer (EC), while its potential prognostic significance has not been characterized so far. Exon7 contains potential binding sites for the two functional splicing regulatory opponents, HNRNPG and HTRA2-BETA1 known to trigger opposite effects on EC outcome. This study served to elucidate the influence of HNRNPG and HTRA2-BETA1 on ERa exon7 splicing regulation and the impact of ERaD7 concentration on type 1 EC outcome. Methods Functional in vitro experiments for HNRNPG and HTRA2-BETA1 in regard to the regulatory impact on endogenous and exogenous ERaD7 splicing were performed. Additionally, real-time PCR determined mRNA levels of ERaD7, HNRNPG and HTRA2-BETA1 in 116 type 1 EC patients. Results HNRNPG and HTRA2-BETA1 were found to be specific regulators of ERa exon7 splicing. While HTRA2-BETA1 promoted exon7 inclusion, HNRNPG antagonized this effect by inducing exon7 skipping (p = 0.004). ERaD7 was detected in 71 out of 116 type 1 EC specimens. Statistical analyses revealed an inverse correlation between ERaD7 mRNA levels and tumor grading (p = 0.029), FIGO stage (p = 0.033) as well as lymph node metastases (p = 0.032), respectively. Furthermore, higher ERaD7 expression could be correlated to an improved disease-specific survival (p = 0.034). Conclusions Our study demonstrates antagonistic regulatory effects of HNRNPG and HTRA2-BETA1 on ERa exon7 splicing with potential impact on type 1 EC clinical outcome due to the consecutively variable expression levels of the ERa isoform D7. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1088-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Marc Hirschfeld
- Department of Obstetrics and Gynecology, University Medical Center Freiburg, Hugstetterstr 55, 79106, Freiburg, Germany. .,German Cancer Consortium (DKTK), Heidelberg, Germany. .,German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Yi Qin Ouyang
- Department of Obstetrics and Gynecology, Tongji Hospital of Tongji University, Shanghai, China.
| | - Markus Jaeger
- Department of Obstetrics and Gynecology, University Medical Center Freiburg, Hugstetterstr 55, 79106, Freiburg, Germany.
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, University Medical Center Freiburg, Hugstetterstr 55, 79106, Freiburg, Germany.
| | | | - Axel Zur Hausen
- Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany. .,Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
| | - Elmar Stickeler
- Department of Obstetrics and Gynecology, University Medical Center Freiburg, Hugstetterstr 55, 79106, Freiburg, Germany.
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Davis VL, Newbold RR, Couse JF, Rea SL, Gallagher KM, Hamilton KJ, Goulding EH, Jefferson W, Eddy EM, Bullock BC, Korach KS. Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol. Reprod Toxicol 2012; 34:512-21. [PMID: 22989549 PMCID: PMC4164054 DOI: 10.1016/j.reprotox.2012.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Revised: 08/02/2012] [Accepted: 08/24/2012] [Indexed: 12/21/2022]
Abstract
ERΔ3 transgenic mice expressing a dominant negative estrogen receptor α (ERα) variant lacking the second zinc finger in the DNA binding domain were developed to examine its potential to inhibit estrogen action in vivo. To investigate if ERΔ3 expression influences uterine carcinogenesis, ERΔ3 transgenic mice were exposed to diethylstilbestrol (DES) on post-natal days 1-5. Neonatal DES treatment induced uterine adenocarcinomas in 81% of 8-month-old ERΔ3 mice compared to 49% of wild-type females (p<0.016). ERΔ3 did not inhibit the expression of the estrogen-responsive progesterone receptor and lactoferrin genes in the presence of ERα or modify their expression in ERα knockout (αERKO) mice. Higher circulating 17β-estradiol levels and non-classical signaling by ERΔ3 may be related to the earlier incidence of uterine cancer. These findings indicate that expression of this ERα variant can influence determining events in uterine cancer development and its natural occurrence in the human uterus would unlikely be protective.
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Affiliation(s)
- Vicki L Davis
- Receptor Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States.
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5
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Abstract
By eliciting distinct transcriptional responses, the oestrogen receptors (ERs) ERα and ERβ exert opposite effects on cellular processes that include proliferation, apoptosis and migration and that differentially influence the development and the progression of cancer. Perturbation of ER subtype-specific expression has been detected in various types of cancer, and the differences in the expression of ERs are correlated with the clinical outcome. The changes in the bioavailability of ERs in tumours, together with their specific biological functions, promote the selective restoration of their activity as one of the major therapeutic approaches for hormone-dependent cancers.
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Affiliation(s)
- Christoforos Thomas
- Center for Nuclear Receptors and Cell Signalling, Department of Biology and Biochemistry, University of Houston, Houston 77204, Texas, USA
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Paul M, Cholewa K, Mazurek U, Witek A, Wilczok T. Estrogen Receptor βΔ6 (ERβΔ6) Isoform in Human Endometrial Hyperplasia and Adenocarcinoma. Cancer Invest 2009; 22:211-8. [PMID: 15199603 DOI: 10.1081/cnv-120030209] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Estrogen receptor (ER)-beta may play a significant role in estrogen action in several human tissues. Estrogen receptor beta may act as a transdominant repressor of ER alpha transcriptional activity trough heterodimers form. Estrogen receptor messenger RNA (mRNA) variants also may be involved in various diseases, including endometrial cancer. The absence of estrogen receptors has often correlated with poor prognosis of endometrial tumors. The objective of the study was to determine the number of mRNA ER beta delta 6 and (wtER beta) in 1 microgram total RNA obtained from tissues of normal, hyperplastic endometrium, and endometrial adenocarcinoma. This study was designed to evaluate possible differences in the ER beta delta 6 and wtER beta messenger RNA (mRNA) level in the normal, hyperplastic endometrium, and endometrial endometrioid adenocarcinoma (G1, G2 morphological degree). Adenocarcinoma showed significantly lower ER beta delta 6 mRNA level than proliferative (p = 0.032) and secretory (p = 0.01) endometrium. A decrease of mRNA wtER beta in endometrial adenocarcinoma (p = 0.006) also was observed.
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Affiliation(s)
- Monika Paul
- Department of Molecular Biology, Biochemistry and Biopharmacy, Medical University of Silesia, Katowice, Poland.
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7
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Wong J, Weickert CS. Transcriptional interaction of an estrogen receptor splice variant and ErbB4 suggests convergence in gene susceptibility pathways in schizophrenia. J Biol Chem 2009; 284:18824-32. [PMID: 19439407 DOI: 10.1074/jbc.m109.013243] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Mounting evidence from clinical and basic research suggests that estrogen signaling may be altered in the brains of people with schizophrenia. Previously, we found that DNA sequence variation in the estrogen receptor (ER) alpha gene, lower ERalpha mRNA levels, and/or blunted ERalpha signaling is associated with schizophrenia. In this study, we asked whether the naturally occurring truncated ERalpha isoform, Delta7, which acts as a dominant negative, can attenuate gene expression induced by the wild-type (WT) receptor in an estrogen-dependent manner in neuronal (SHSY5Y) and non-neuronal (CHOK1 and HeLa) cells. In addition, we determined the extent to which ERalpha interacts with NRG1-ErbB4, a leading schizophrenia susceptibility pathway. Reductions in the transcriptionally active form of ErbB4 comprising the intracytoplasmic domain (ErbB4-ICD) have been found in schizophrenia, and we hypothesized that ERalpha and ErbB4 may converge to control gene expression. In the present study, we show that truncated Delta7-ERalpha attenuates WT-ERalpha-driven gene expression across a wide range of estrogen concentrations in cells that express functional ERalpha at base line or upon co-transfection of full-length ERalpha. Furthermore, we find that ErbB4-ICD can potentiate the transcriptional activity of WT-ERalpha at EREs in two cell lines and that this potentiation effect is abolished by the presence of Delta7-ERalpha. Immunofluorescence microscopy revealed nuclear co-localization of WT-ERalpha, Delta7-ERalpha, and ErbB4-ICD, whereas immunoprecipitation assays showed direct interaction. Our findings demonstrate convergence between ERalpha and ErbB4-ICD in the transcriptional control of ERalpha-target gene expression and suggest that this may represent a convergent pathway that may be disrupted in schizophrenia.
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Affiliation(s)
- Jenny Wong
- Schizophrenia Research Institute, Sydney, New South Wales 2052, Australia
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Mylonas I, Makovitzky J, Friese K, Jeschke U. Immunohistochemical labelling of steroid receptors in normal and malignant human endometrium. Acta Histochem 2009; 111:349-59. [PMID: 19195687 DOI: 10.1016/j.acthis.2008.11.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
For several years it was generally believed that only a single estrogen receptor (ER) and progesterone receptor (PR) existed. However, the discovery of a new ER (ERbeta) with specificity for estrogens has induced new insights in the estrogen signalling system. Moreover, PR is expressed as two major isoforms, PR-A and PR-B that arise from alternative transcriptional starting sites within the same gene. Although PR-A and PR-B were thought to occur in similar amounts, it is now clear that they are differentially expressed and thus have distinct functions in several human tissues, including human endometrium. The ER and PR expression and distribution pattern might play an important role in normal endometrial function and pathogenesis and the expression and relationship of the two distinct ER's and PR's could be of essential clinical implications. Moreover, the imbalance in ERalpha/ERbeta expression and the PR-A/PR-B ratio might play an important role in endometrial transition and subsequently influence endometrial pathogenesis. The knowledge of the pattern of steroid receptors in human endometrial tissue is of extreme importance, since it might start a new field in hormone therapy of endometrial cancer.
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Doll A, Abal M, Rigau M, Monge M, Gonzalez M, Demajo S, Colás E, Llauradó M, Alazzouzi H, Planagumá J, Lohmann MA, Garcia J, Castellvi S, Ramon y Cajal J, Gil-Moreno A, Xercavins J, Alameda F, Reventós J. Novel molecular profiles of endometrial cancer-new light through old windows. J Steroid Biochem Mol Biol 2008; 108:221-9. [PMID: 18061438 DOI: 10.1016/j.jsbmb.2007.09.020] [Citation(s) in RCA: 151] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Endometrial carcinoma (EC) is the most common gynecological malignancy in the western world. A widely accepted dualistic model, which has been established on a morphological basis, differentiates EC into two broad categories: Type I oestrogen-dependent adenocarcinoma with an endometrioid morphology and Type II non-oestrogen-dependent EC with a serous papillary or clear cell morphology. Molecular genetic evidence indicates that endometrial carcinoma, as described in other malignancies, likely develops as the result of a stepwise accumulation of alterations in cellular regulatory pathways, such as oncogene activation and tumor suppressor gene inactivation, which lead to dysfunctional cell growth. These molecular alterations appear to be specific in Type I and Type II cancers. In type I endometrioid endometrial cancer, PTEN gene silencing in conjunction with defects in DNA mismatch repair genes, as evidenced by the microsatellite instability phenotype, or mutations in the K-ras and/or beta-catenin genes, are recognized major alterations, which define the progression of the normal endometrium to hyperplasia, to endometrial intraepithelial neoplasia, and then on to carcinoma. In contrast, Type II cancers show mutations of TP53 and Her-2/neu and seem to arise from a background of atrophic endometrium. Nevertheless, despite the great effort made to establish a molecularly-based histological classification, the following issues must still be clarified: what triggers the tumor cells to invade the myometrium and what causes vascular or lymphatic dissemination, finally culminating in metastasis? RUNX1, a transcription factor, was recently identified as one of the most highly over-expressed genes in a microarray study of invasive endometrial carcinoma. Another candidate gene, which may be associated with an initial switch to myometrial infiltration, is the transcription factor ETV5/ERM. These studies, as well as those conducted for other genes possibly involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, could help in understanding the differences in the biology and the clinical outcome among histological types.
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Affiliation(s)
- A Doll
- Unitat de Recerca Biomedica, Research Institute Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, Barcelona, Spain
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Gründker C, Günthert AR, Emons G. Hormonal heterogeneity of endometrial cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008; 630:166-88. [PMID: 18637491 DOI: 10.1007/978-0-387-78818-0_11] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Endometrial cancer is the most common malignant tumor of the female genital tract in the developed world. Increasing evidence suggests that the majority of cases can be divided into two different types ofendometrial cancer based on clinico-pathological and molecular characteristics. Type I is associated with an endocrine milieu of estrogen predominance. These tumors are ofendometroid histology and develop from endometrial hyperplasia. They have good prognosis and are sensitive to endocrine treatment. Type II endometrial cancers are not associated with a history of unopposed estrogens and develop from the atrophic endometrium of elderly women. Mainly, they are of serous papillary or clear cell morphology, have a poor prognosis and do not react to endocrine treatment. Both types of endometrial cancer probably differ markedly with regard to the molecular mechanisms of transformation. The transition from normal endometrium to a malignant tumor is thought to involve a stepwise accumulation of alterations in cellular mechanisms leading to dysfunctional cell growth. This chapter reviews the current knowledge of the molecular mechanisms commonly associated with development of type I and type II endometrial cancer.
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Affiliation(s)
- Carsten Gründker
- Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany
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11
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Abstract
Endometrial cancer is the most common gynaecological cancer, and is associated with endometrial hyperplasia, unopposed oestrogen exposure and adjuvant therapy for breast cancer using selective oestrogen-receptor modulators (SERMs), particularly tamoxifen. Oestrogen and SERMs are thought to be involved in endometrial carcinogenesis through their effects on transcriptional regulation. Ultimately, oestrogen and SERMs affect the transduction of cellular signalling pathways that govern cell growth and proliferation, through downstream effectors such as PAX2 (paired box 2).
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Affiliation(s)
- Yongfeng Shang
- Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China.
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12
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O'Toole SA, Dunn E, Sheppard BL, Klocker H, Bektic J, Smyth P, Martin C, Sheils O, O'Leary JJ. Genome-wide analysis of deoxyribonucleic acid in endometrial cancer using comparative genomic hybridization microarrays. Int J Gynecol Cancer 2006; 16:834-42. [PMID: 16681770 DOI: 10.1111/j.1525-1438.2006.00530.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
The aim of this study was to identify amplified oncogenes in endometrial cancer using array-based comparative genomic hybridization (array CGH). Despite its prevalence, the molecular mechanisms of endometrial carcinogenesis are still poorly understood. The selected array CGH allows the simultaneous examination of 58 oncogenes commonly amplified in human cancers and is capable of achieving increased mapping resolution compared with conventional CGH. A subset of 8 specimens from a bank of 60 malignant and normal specimens was selected for array analysis to identify potential genes of interest. TaqMan polymerase chain reaction was carried out on the 60 specimens to examine if aberrations at the genomic level correlated with gene expression and to compare expression in normal and malignant samples. Oncogenes amplified in the endometrial cancers included AR, PIK3CA, MET, HRAS, NRAS, D17S1670, FGFR1, CTSB, RPS6KB1, LAMC2, MYC, PDGFRA, FGF4/FGF3, PAKI, and FGR. Three genes were examined at the messenger RNA level. AR and PIK3CA were higher in normal specimens, and MET was higher in malignant samples, suggesting a role for MET in endometrial cancer. Newer arrays examining more genes and larger sample numbers are necessary to elucidate the carcinogenic pathway in endometrial cancer.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma, Papillary/genetics
- Adenocarcinoma, Papillary/metabolism
- Adenocarcinoma, Papillary/pathology
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Adenosquamous/genetics
- Carcinoma, Adenosquamous/metabolism
- Carcinoma, Adenosquamous/pathology
- Case-Control Studies
- Cystadenocarcinoma, Serous/genetics
- Cystadenocarcinoma, Serous/metabolism
- Cystadenocarcinoma, Serous/pathology
- DNA/genetics
- DNA, Neoplasm/genetics
- Endometrial Neoplasms/genetics
- Endometrial Neoplasms/metabolism
- Endometrial Neoplasms/pathology
- Endometrium/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Genome, Human
- Humans
- In Situ Hybridization, Fluorescence
- Middle Aged
- Nucleic Acid Hybridization
- Oligonucleotide Array Sequence Analysis
- Oncogenes/genetics
- Tumor Cells, Cultured
- Up-Regulation
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Affiliation(s)
- S A O'Toole
- Trinity College Department of Obstetrics and Gynaecology, University of Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland.
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13
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Ryan AJ, Susil B, Jobling TW, Oehler MK. Endometrial cancer. Cell Tissue Res 2005; 322:53-61. [PMID: 15947972 DOI: 10.1007/s00441-005-1109-5] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2004] [Accepted: 03/01/2005] [Indexed: 10/25/2022]
Abstract
Endometrial cancer is the most common gynaecological malignancy in the developed world. The majority of cases can be divided into two broad categories based on clinico-pathological and molecular characteristics; Type I oestrogen-dependent with endometrioid morphology and Type II non-oestrogen-dependent with serous papillary or clear cell morphology. As has been described for other malignancies, such as colorectal carcinoma, the transition from normal endometrium to carcinoma is thought to involve a stepwise accumulation of alterations in cellular regulatory pathways leading to dysfunctional cell growth. This article reviews the current knowledge of the molecular changes commonly associated with endometrial cancer and presents possible progression models.
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Affiliation(s)
- Andrew J Ryan
- Department of Anatomical Pathology, Monash Medical Centre, Clayton, Victoria, Australia
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14
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Abstract
As early as the 1800s, the actions of estrogen have been implicated in the development and progression of breast cancer. The estrogen receptor (ER) was identified in the late 1950s and purified a few years later. However, it was not until the 1980s that the first ER was molecularly cloned, and in the mid 1990s, a second ER was cloned. These two related receptors are now called ERalpha and ERbeta, respectively. Since their discovery, much research has focused on identifying alterations within the coding sequence of these receptors in clinical samples. As a result, a large number of naturally occurring splice variants of both ERalpha and ERbeta have been identified in normal epithelium and diseased or cancerous tissues. In contrast, only a few point mutations have been identified in human patient samples from a variety of disease states, including breast cancer, endometrial cancer, and psychiatric diseases. To elucidate the mechanism of action for these variant isoforms or mutant receptors, experimental mutagenesis has been used to analyze the function of distinct amino acid residues in the ERs. This review will focus on ERalpha and ERbeta alterations in breast cancer.
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Affiliation(s)
- Matthew H Herynk
- Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
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Zhao XH, Gu SZ, Liu SX, Pan BR. Expression of estrogen receptor and estrogen receptor messenger RNA in gastric carcinoma tissues. World J Gastroenterol 2003; 9:665-9. [PMID: 12679906 PMCID: PMC4611424 DOI: 10.3748/wjg.v9.i4.665] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study estrogen receptor (ER) and estrogen receptor messenger RNA (ERmRNA) expression in gastric carcinoma tissues and to investigate their association with the pathologic types of gastric carcinoma.
METHODS: The expression of ER and ERmRNA in gastric carcinoma tissues (15 males and 15 females, 42-70 years old) was detected by immunohistochemistry and in situ hybridization, respectively.
RESULTS: The positive rate of ER (immunohistochemistry) was 33.3% in males and 46.7% in females. In Borrmann IV gastric carcinoma ER positive rate was greater than that in other pathologic types, and in poorly differentiated adenocarcinoma and signet ring cell carcinoma the positive rates were greater than those in other histological types of both males and females (P < 0.05). The ER was more highly expressed in diffused gastric carcinoma than in non-diffused gastric carcinoma (P < 0.05). The ER positive rate was also related to regional lymph nodes metastases (P < 0.05), and was significantly higher in females above 55 years old, and higher in males under 55 years old (P < 0.05). The ERmRNA (in situ hybridization) positive rate was 73.3% in males and 86.7% in females. The ERmRNA positive rates were almost the same in Borrmann I, II, III and IV gastric carcinoma (P > 0.05). ERmRNA was expressed in all tubular adenocarcinoma, poorly differentiated adenocarcinoma and signet ring cell carcinoma (P < 0.05). The ERmRNA positive rate was related to both regional lymph nodes metastases and gastric carcinoma growth patterns, and was higher in both sexes above 55 years old but without statistical significance (P > 0.05). The positive rate of ERmRNA expression by in situ hybridization was higher than that of ER expression by immunohistochemistry (P < 0.05).
CONCLUSION: ERmRNA expression is related to the pathological behaviors of gastric carcinoma, which might help to predict the prognosis and predict the effectiveness of endocrine therapy for gastric carcinoma.
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Affiliation(s)
- Xin-Han Zhao
- Department of Medical Oncology, First Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
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Cobellis L, Reis FM, Driul L, Vultaggio G, Ferretti I, Villa E, Petraglia F. Estrogen receptor alpha mRNA variant lacking exon 5 is co-expressed with the wild-type in endometrial adenocarcinoma. Eur J Obstet Gynecol Reprod Biol 2002; 102:92-5. [PMID: 12039098 DOI: 10.1016/s0301-2115(01)00576-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Endometrial adenocarcinoma is a typical estrogen-dependent neoplasia. The molecular mechanisms underlying carcinogenesis in the endometrium are still largely unknown. Recently, estrogen receptor (ER) mRNA splicing variants have been investigated in several normal and neoplastic human tissues. It has been suggested that the variant receptors compete with the wild-type receptors and thereby modulate the effects of estrogens and related steroids. OBJECTIVE To investigate the possible expression of the ER alpha mRNA variant-type lacking exon 5 (ERDelta5) in endometrial adenocarcinoma and peritumoral tissues, non-neoplastic endometrium of healthy women served as control. STUDY DESIGN The study included 16 patients divided in two groups. The first group (n=6) was submitted to hysteroscopy and endometrial biopsy for metrorrhage, showing normal proliferative (n=2) or secretory (n=4) endometrium, the second group (n=10) included patients submitted to hysterectomy for endometrial adenocarcinoma (stages Ib-IIIb). In this latter group, specimens from peritumoral tissues were also analyzed (n=3). Characterization of the variant and wild-type alpha estrogen receptor transcripts was performed by RT-PCR with primers located in exons 4 and 6, followed by southern hybridization with probes directed to a specific 29 nucleotide sequence of exon 6, internal to the amplified fragments. RESULTS The ER alpha mRNA variant was co-expressed with the wild-type ER in five or six samples of non-neoplastic endometrium and in 10/10 cases of adenocarcinoma, with a more intense hybridization signal corresponding to the wild-type 439bp band compared to the variant-type 300bp band. Specimens from peritumoral tissue also expressed the variant ERDelta5 along with wild-type ER. CONCLUSION The presence of alpha mRNA variant lacking exon 5 in both normal and endometrial adenocarcinoma do not support a major role of variant estrogens receptors in the biology of endometrial cancer.
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Affiliation(s)
- Luigi Cobellis
- Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Siena, Italy
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Horvath G, Leser G, Helou K, Henriksson M. Function of the exon 7 deletion variant estrogen receptor alpha protein in an estradiol-resistant, tamoxifen-sensitive human endometrial adenocarcinoma grown in nude mice. Gynecol Oncol 2002; 84:271-9. [PMID: 11812086 DOI: 10.1006/gyno.2001.6509] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND In addition to hormone and DNA binding, interactions, including competition with other proteins, appear to be a critical component of transcriptional regulation by the estrogen receptor alpha (ER(alpha)). In vitro studies suggest that exon deletion (Delta exon) variant forms of ER(alpha) may also play an important role in determining the progression from hormone dependence to hormone independence in receptor positive tumors. METHODS We investigated the presence of ERalpha mRNA and protein variants and their possible role in a moderately differentiated human endometrial adenocarcinoma grown in nude mice. In addition to wild-type (wt), RT-PCR assay of the tumor revealed the presence of two mRNA variants, a low concentration of Delta5 and a high concentration of Delta7 ER(alpha). We detected wt, Delta7, and Delta5,7 mRNA by sequencing the transcripts after stable transfection of three HeLa cells with either splice variant. The linked in vitro translation/transcription assay of the transfected cells and the Western blot analysis of the original tumor generated both wt (66 kDa) and Delta7 (52 kDa), Delta5,7 (46 kDa) ER(alpha) proteins. RESULTS Tumor growth was characterized as estradiol and progesterone resistant but tamoxifen sensitive, i.e., neither estradiol nor progesterone treatment altered the growth rate, whereas tamoxifen treatment significantly increased the tumor volume doubling time. Estradiol treatment decreased the wt and increased the Delta7 variant ER(alpha) protein expression significantly in a dose-dependent manner. Tamoxifen treatment, however, increased the expression of both proteins whereas progesterone had no effect. Estradiol treatment did not influence expression of the Delta5,7 variant protein, which increased significantly in the tamoxifen-treated tumors. Gel mobility shift assays revealed that both wt and Delta7 ER(alpha) proteins bind to the consensus DNA sequence, whereas the Delta5,7 variant protein did not. CONCLUSIONS We conclude that estradiol, tamoxifen, and progesterone regulate wt and variant ER(alpha) mRNA and protein expression separately and differently and that this hormonal regulation probably occurs, via different mechanisms, at the transcriptional or posttranscriptional level. The Delta7 variant ER(alpha) may play a crucial role in the determination of hormone sensitivity and thus in the outcome of hormone treatment of human endometrial adenocarcinomas.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Alternative Splicing
- Animals
- Antineoplastic Agents, Hormonal/pharmacology
- Cell Division/drug effects
- DNA, Neoplasm/genetics
- DNA, Neoplasm/metabolism
- Drug Resistance, Neoplasm
- Endometrial Neoplasms/genetics
- Endometrial Neoplasms/metabolism
- Endometrial Neoplasms/pathology
- Estradiol/pharmacology
- Estrogen Receptor alpha
- Exons/genetics
- Female
- Gene Deletion
- Humans
- Mice
- Mice, Nude
- Neoplasm Transplantation
- Protein Isoforms
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Receptors, Estrogen/genetics
- Receptors, Estrogen/physiology
- Receptors, Progesterone/biosynthesis
- Signal Transduction/physiology
- Tamoxifen/pharmacology
- Transfection
- Transplantation, Heterologous
- Tumor Cells, Cultured
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Affiliation(s)
- György Horvath
- Gynecologic Oncology Section, Sahlgrenska University Hospital, Gothenburg, Sweden.
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