Correlation between the DNA global methylation status and progesterone receptor expression in normal endometrium, endometrioid adenocarcinoma and precursors

Ghabreau, Lina; Roux, Jean-Paul; Niveleau, Alain; B, Fontanière; Mahé, Cédric; Mokni, Moncef; Frappart, Lucien

doi:10.1007/s00428-004-1059-4

Cited by 47 publications

(32 citation statements)

References 38 publications

(50 reference statements)

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“…Global DNA methylation was also examined in fixed sections of PHM tissue and placenta using an antibody directed against 5-methylcytosine (Ghabreau et al, 2004). Results indicated a relatively homogeneous level of DNA methylation among PHM sections (Figure 1ac) with an intensity similar to that obtained in normal placenta (Figure 1b and c compared to Figure 1d).…”

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confidence: 69%

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Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

Ballestar

Fraga

et al. 2006

Oncogene

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In human post-natal somatic cells, low global levels of DNA methylation have been associated with the hypomethylation of several repetitive elements, a feature that has been proposed to be a surrogate epigenetic marker. These data, mainly derived from the analysis of cancer cells, suggest a potential association between loss of cellgrowth control and altered differentiation with hypomethylation of repetitive sequences. Partial hydatidiform moles (PHMs) can be used as an alternative model for investigating this association in a non-tumorigenic context. This gestational disease is characterized by abnormal overgrowth and differentiation of the placenta and spontaneous abortion. Here, we comprehensively analyse the DNA methylation of these trophoblastic tissues in both PHM and normal placenta at global and sequencespecific levels. Analysis of the global 5-methylcytosine content and immunohistochemistry indicate that PHM and normal placenta have identical global levels of DNA methylation. In contrast, bisulfite genomic sequencing shows that, whereas Alu, NBL2 and satellite 2 repetitive elements are equally methylated, LINE-1 sequences are hypermethylated in PHM tissues (B2-fold relative to normal placenta). Interestingly, altered demethylation is also found in triploid diandric embryos that originate from dispermic fertilization of an oocyte, a common event responsible for most PHMs. In conclusion, alterations of DNA methylation do not seem to be randomly distributed in PHM, as several repeated elements remain unaltered, whereas LINE-1 sequences are hypermethylated. In addition, our findings suggest that the hypomethylation of repetitive elements in cancer is directly linked to the neoplasic process and not a simple consequence of loss of growth control observed in most of the cancer cells.

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confidence: 69%

“…Experimental alterations of the zygote epigenome have provided a link between epigenetic marks and further zygote (Tavassoli and Devilee, 2003). Immunohistochemistry using anti 5-methylcytosine antibodies was carried out as described previously (Ghabreau et al, 2004). Specific hypermethylation of LINE-1 elements D Perrin et al development (Morgan et al, 2005).…”

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confidence: 99%

Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

Ballestar

Fraga

et al. 2006

Oncogene

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“…Significantly higher DNA methylation levels have been detected in the proliferative phase when compared with the secretory phase in women (Ghabreau et al 2004). In addition, both mRNA and protein levels of ESR2 are downregulated in the endometrial stromal cells by DNA methylation of the promoter (Xue et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…nuclear hormone receptors, are influenced by DNA methylation in the endometrium, myometrium, ovary, and breast (Piva et al 1989, Lapidus et al 1996, Hori et al 2000, Ghabreau et al 2004, Mehrotra et al 2004, Ren et al 2007, Suzuki et al 2008, Li et al 2010, Wei et al 2012. These finding further suggest that the levels of DNMTs in endometrial tissues are regulated by estrogen and progesterone during menstruation.…”

Section: Protein Treatment Stromamentioning

confidence: 96%

Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency

Ding

He²,

Liu³

et al. 2012

Reproduction

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We have characterized the uterine expression of DNA methyltransferases (DNMTs) during early pregnancy in mice and determined whether a folate-deficient diet (FDD) can affect DNMTs in this context. Within endometrial cells, expressions of DNMT (cytosine-5) 1 (Dnmt1),Dnmt3a, andDnmt3bwere significantly elevated during the prereceptive phase of pregnancy but generally returned to baseline levels during receptive and postimplantation periods. As such, the transcription of DNMT genes is temporally regulated during early pregnancy. When comparisons were made between implantation sites (IS) and inter-IS on day 5 of pregnancy, lower levels ofDnmt3awere detected at IS. Comparisons between IS and inter-IS did not reveal significant expression differences for other DNMT genes. When tissue sections were examined, DNMT3A was specifically lower in the stroma of IS. Reduced DNMT1 and DNMT3B levels were also observed in the luminal and glandular epithelia of IS, whereas no obvious differences in the stroma were detected. In pseudo-pregnant mice subjected to a FDD, levels ofDnmt1andDnmt3a(but notDnmt3b) were significantly upregulated in endometrial tissues, as compared with controls. When tissues from these folate-deficient mice were examined, DNMT1 levels were elevated in both the luminal and glandular epithelia, whereas DNMT3A was upregulated in the luminal epithelium and the stroma. A slight increase in DNMT3B levels was detected in the glandular epithelium. These results indicate that DNMTs may regulate the transcription of endometrial genes associated with embryo implantation and that levels of DNMTs are affected by dietary folate in mice.

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“…The expression of both PR and pS2 is under estrogen control (20 -22). Ghabreau et al (23) recently reported that the expression of PR gradually increases in non -atypical and atypical endometrial hyperplasia and reaches the highest level in grade 1 endometrioid adenocarcinoma, then decreases stepwise in grade 2 and grade 3 endometrioid tumors. Koshiyama et al (24) has reported that the expression of pS2 increases progressively from normal endometrium to endometrial hyperplasia and well-differentiated carcinoma, but pS2 expression decreases stepwise in grade 2 and grade 3 endometrioid carcinomas and becomes undetectable in nonendometrioid tumors.…”

Section: Eig121 a Novelmentioning

confidence: 99%

Identification of a Novel Estrogen-Regulated Gene, EIG121, Induced by Hormone Replacement Therapy and Differentially Expressed in Type I and Type II Endometrial Cancer

Deng

Broaddus

McCampbell

et al. 2005

Clinical Cancer Research

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Purpose:The identification of genes and pathways that are affected by estrogenization may shed light on the mechanisms of estrogen action. Here, we describe the expression pattern of a novel estrogen-induced gene, EIG121, in distinct types of endometrial cancer. Experimental Design: EIG121was identified by cDNA microarray analysis of endometrial RNA from women receiving either placebo or estrogen replacement therapy. The expression level of EIG121 was then measured by real-time quantitative reverse transcription-PCR in benign, hyperplastic, and malignant endometrial samples. A polyclonal antibody was used to detect EIG121 protein by immunohistochemistry. Results: In postmenopausal endometrium, estrogen replacement therapy with Premarin and synthetic estrogen sulfate conjugates induced the expression of EIG1212-and 3-fold, respectively. In premenopausal endometrium, the expression of EIG121was higher in the estrogen-dominated proliferative phase than the secretory phase. In endometrial complex, hyperplasia, and endometrioid adenocarcinoma, neoplastic proliferations associated with estrogen excess, the expression of EIG121 was significantly elevated (on average 3.8-fold in hyperplasias and 21-fold in grade 1 tumors). Although the level of EIG121mRNA in grade 3 endometrioid carcinoma was still 3.5-fold of that in benign endometrium, EIG121 expression tended to decline with increasing tumor grade and disease stage. Immunohistochemistry showed faint staining of normal endometrial epithelium, but intense staining of endometrioid tumors. In sharp contrast, EIG121 expression was significantly suppressed in both uterine papillary serous carcinoma and uterine malignant mixed mullerian tumor, two tumors not associated with estrogen exposure, to <5% of the level in benign endometrium. Conclusions: Our results suggest that EIG121is a good endometrial biomarker associated with a hyperestrogenic state and estrogen-related type I endometrial adenocarcinoma.The endometrium, a complex tissue that lines the uterine cavity, is composed of both glandular and stromal elements. Endometrial carcinoma, which arises from the epithelial component, is the most common gynecologic malignancy and accounts for the majority of the estimated 40,880 new cases and 7,310 related deaths from uterine corpus cancer among women in the U.S. in 2005 (1). Clinicopathologic studies have shown that there are two major types of endometrial carcinoma: type I, an estrogen-related, low-grade endometrioid neoplasm that occurs in younger, premenopausal women and is associated with low clinical stage; and the more clinically aggressive type II, which is usually estrogen-independent, shows nonendometrioid histology, and occurs in postmenopausal women (2). Based on the distinctive clinical and histologic features of the two types of endometrial carcinomas, a dualistic model of carcinogenesis has been proposed for type I and type II tumors (3 -5). Type I endometrial carcinomas are thought to develop in response to prolonged and unopposed estrogen stimulation...

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Correlation between the DNA global methylation status and progesterone receptor expression in normal endometrium, endometrioid adenocarcinoma and precursors

Cited by 47 publications

References 38 publications

Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency

Identification of a Novel Estrogen-Regulated Gene, EIG121, Induced by Hormone Replacement Therapy and Differentially Expressed in Type I and Type II Endometrial Cancer

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