Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment

Zhou, Xizhao; Dowdy, Sean C.; Podratz, Karl C.; Jiang, Shi Wen

doi:10.1016/j.ygyno.2007.06.019

Cited by 51 publications

(39 citation statements)

References 103 publications

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“…In addition to distinct genetic mutations found in EAC, epigenetic mechanisms may play an important role in the pathogenesis of this tumor (33,34). Silencing of gene expression by CpG hypermethylation has been shown to be an early event in cancer development, and it can even precede the neoplastic process (35).…”

Section: Discussionmentioning

confidence: 99%

Prostate-Specific Membrane Antigen Expression Is a Potential Prognostic Marker in Endometrial Adenocarcinoma

Mhawech‐Fauceglia

Smiraglia²,

Bshara³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The aim of this study was to determine the role of prostate-specific membrane antigen (PSMA) as a prognostic marker in endometrial adenocarcinoma (EAC) and to explore whether its down-regulation could be due to epigenetic mechanism. First, we examined the expression and the prognostic value of PSMA by semiquantitative reverse transcription-PCR and immunohistochemistry in EAC tissue samples. Second, to explore the role of CpG methylation in down-regulation PSMA in EAC, we evaluated PSMA CpG island methylation using methylation-specific PCR in cells lines and in a subset of patients' samples. Furthermore, association of the status of tumor methylation to the clinical and histologic variables was also evaluated. Higher PSMA mRNA levels were associated with stage I (P = 0.046) and PSMA protein intensity by immunohistochemistry (P = 0.032). In multivariate analysis, loss of PSMA expression was associated with a worse disease-free survival (P = 0.02). PSMA was methylated in prostate cell lines (DU145 and PC3) and endometrial cell lines. In addition, PSMA was methylated in 5 of 18 samples (all 5 had low PSMA mRNA value). There was a significant association between PSMA methylation and loss of protein expression by immunohistochemistry and PSMA-RNA level with P value of 0.036 and 0.011, respectively. In addition, there was an association between PSMA methylation and tumor size (P = 0.025). In summary, (a) PSMA is underexpressed in advanced stage EAC, (b) loss of PSMA expression can be considered as a prognostic marker in patients with EAC, and (c) loss of PSMA expression in a subset of EAC cases could be due to epigenetic silencing. (Cancer Epidemiol Biomarkers Prev 2008;17(3):571 -7)

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Section: Discussionmentioning

confidence: 99%

Prostate-Specific Membrane Antigen Expression Is a Potential Prognostic Marker in Endometrial Adenocarcinoma

Mhawech‐Fauceglia

Smiraglia²,

Bshara³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Breast and reproductive tract cancers and osteoporosis have drawn considerable attention as candidates for the effects of fetal programming (Barbieri, 2008;Michels, Xue, Terry, and Willett, 2006;Zhou, Dowdy, Podratz, and Jiang, 2007). This in turn suggests that the expression patterns of steroid receptor genes may also be subject to epigenetic regulation (Fleury, Gerus, Lavigne, Richard-Foy, and Bystricky, 2008;Jordan, 2007;Leader, Wang, Fu, and Pestell, 2006;Wu, Strawn, Basir, Halverson, and Guo, 2006).…”

Section: Epigenetic Programming Of Energy Metabolismmentioning

confidence: 99%

Fetal programming and fetal psychology

Ellison

2010

Infant and Child Development

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The introduction of the "fetal programming hypothesis," first in epidemiology, subsequently in a broad range of disciplines concerned with developmental biology, has generated new interest in phenotypic plasticity, the mechanisms that govern it, and its place in evolutionary biology. A number of epidemiological studies link small size at birth, assumed to be a consequence of constrained prenatal energy availability, with adverse effects on the risk of chronic diseases later in life. The cluster of chronic diseases associated with the metabolic syndrome and alterations of glucose metabolism are particularly implicated. Recent evidence suggests that epigenetic modification of gene expression affecting the hypothalamic-pituitary-adrenal (HPA) axis may be involved in these effects. In animal studies epigenetic alteration of HPA axis activity and responsiveness is associated with changes in adult behavior and stress responsiveness.The potential for similar effects to contribute to psychological and psychiatric outcomes has been explored in a number of contexts, including famine exposure, observed covariance with birth weight, and prenatal dexamethasone treatment of fetuses at risk of congenital adrenal hyperplasia. While fetal programming effects have now been widely demonstrated across species and human populations, the adaptive significance of these effects is still a matter of debate.Life is integrated, cumulative, and continuous, not episodic, static, or discrete.Behavioral scientists rarely forget this, but biologists often do. Developmental biology is the one domain of the life sciences where the organism as a progressively unfolding phenomenon is a central concept. The reemergence of developmental biology as a vigorous discipline, intersecting in important ways with genetics (Badayev, 2008), evolution (West-Eberhard, 2003), and epidemiology (Barker, 1994;Gluckman and Hanson, 2006;Kuh, Ben-Shlomo, Lynch, Hallqvist, and Power, 2003), has injected new energy and new ideas into all those fields. Within epidemiology a seminal impact of this new attention to developmental biology has been in the formulation of the "fetal programming hypothesis," also known as the "fetal origins hypothesis," or, more generally, as the "developmental origins of health and disease" (DOHaD). Simply put, this hypothesis suggests that conditions very early in development, even in utero, can leave lasting imprints of an organism's physiology, imprints that may affect susceptibility to diseases with onsets that may occur many decades later (Barker, Eriksson, Forsen, and Osmond, 2002;.The concept of fetal programming is, of course, not new. Behavioral endocrinologists and neuroscientists, for example, have long recognized "organizational effects" of prenatal androgen hormones in "programming" certain aspects of reproductive axis function and reproductive behavior that emerges later in an animal's life (Nelson, 2005). "Critical periods" in development, including fetal development, are familiar

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“…Common genetic abnormalities in EC include mutations in PTEN, K-RAS, PI3CA and CTNNB1; TP53 mutations are very rare (Prat et al, 2007). Epigenetic studies have linked hypermethylation to the loss of expression of DNA repair enzymes, MLH1 and O6-methylguanine DNA methyltransferase (MGMT), the tumor suppressors, PTEN, p53 and TIG1, the progesterone receptor, the b-catenin/Wnt signaling regulator, APC (adenomatous polyposis coli), the transcription factor, C/EBPa, and the differentiation gene, HoxA10 (Furlan et al, 2006;Shang, 2006;Yoshida et al, 2006;Zhou et al, 2007). Alternatively, hypomethylation has been described as a contributing factor for oncogene overexpression in EC.…”

mentioning

confidence: 99%

DNA methylation inhibits p53-mediated survivin repression

2009

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The molecular progression of endometrial cancer is poorly understood, and both genetic and epigenetic factors play a role. Survivin is a member of the inhibitor of apoptosis (IAP) gene family and contains a canonical CpG island that has been described as epigenetically regulated. As survivin is overexpressed in endometrial tumors, we hypothesized that hypomethylation could explain this expression pattern. Surprisingly, methylation-specific PCR and pyrosequencing showed that survivin was hypermethylated in endometrial tumors and correlated with increased survivin expression. We speculated that methylation could inhibit the binding of p53, a repressor of survivin expression. Our data indicates that demethylation of the survivin promoter by decitabine results in p53-dependent survivin repression and that p53 binding can be inhibited by DNA methylation. We are the first to report survivin de-repression by DNA methylation. We also present microarray data, which suggest that de-repression by methylation is a general mechanism of p53 regulation. Demethylation induced by decitabine is traditionally thought to be active in tumors by allowing the reexpression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.

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Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment

Cited by 51 publications

References 103 publications

Prostate-Specific Membrane Antigen Expression Is a Potential Prognostic Marker in Endometrial Adenocarcinoma

Prostate-Specific Membrane Antigen Expression Is a Potential Prognostic Marker in Endometrial Adenocarcinoma

Fetal programming and fetal psychology

DNA methylation inhibits p53-mediated survivin repression

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