Risk For Development Of Endometrial Cancer Research Articles

Analysis of the Expression of LSF Transcription Factor in the Regulation of Transcription and TSG101 during the Neoplastic Transformation of Endometrial Cells.

Previous research indicates that carcinogenesis involves disrupting the functions of numerous genes, including factors involved in the regulation of transcription and cell proliferation. For these reasons, in endometrial carcinogenesis, we decided to investigate the expression of TSG101 (a suppressor of tumor transformation) and LSF (a transcription factor involved in numerous cellular processes, such as cell cycle regulation, cell growth, development, and apoptosis). LSF may be involved in the regulation of TSG101 expression. The research material consisted of endometrial cancer samples from 60 patients. The control group consisted of normal endometrium samples donated by 60 women undergoing surgery for benign diseases of the female reproductive organs. The samples were subjected to immunohistochemical staining with antibodies specific to TSG101 and LSF. Specific antibodies were used to identify TSG101 and LSF in the examined histopathological preparations. An approximately 14-fold lower risk of endometrial cancer development was observed in patients with TSG expression in more than 75% of the assessed cells (4% vs. 36%; OR = 0.07; p = 0.0182). There was a four-fold lower risk of endometrial cancer development in patients with LSF expression in more than 50% of the assessed cells (32% vs. 64%; OR = 0.26; p = 0.0262). A more than three-fold lower risk of endometrial cancer development was observed in patients with LSF expression in more than 75% of the assessed cells (24% vs. 52%; OR = 0.29; p = 0.0454). Endometrial cancer was diagnosed in those with a lower level of TSG101 expression than in those with a cancer-free endometrium. Decreased expression of TSG101 may be a marker of endometrial cancer, and increased expression of LSF when diagnosed with endometrial cancer may indicate greater advancement of the disease. These markers might be used as diagnostic and prognostic markers-however, there is a lack of a correlation between them.

Insights to the neural response to food cues in class III compared with class I and II obese adults using a sample of endometrial cancer survivors seeking weight loss

BackgroundThe rates of severe or Class III obesity (BMI ≥ 40.0 kg/m2) and endometrial cancer (EC) incidence and mortality have been increasing significantly in the United States. Adults with severe obesity are more likely to die and women with severe obesity have a higher risk of EC development and mortality than those with Class I/II obesity (BMI: 30–<40 kg/m2). However, no prior studies have evaluated the neural response to food cues by obesity severity/class in adults with or without cancer.MethodsWe conducted a functional magnetic resonance imaging visual food cue task in 85 obese Stage I EC survivors who were seeking weight loss in a lifestyle intervention at baseline. We evaluated the neural response to high-calorie vs. non-food images after an overnight fast (fasted state) and after eating a standardized meal (fed state), and grouped patients by obesity class (Class I/II: n = 38; Class III: n = 47).ResultsIn the fasted state, we found increased activation in several regions including the dorsolateral prefrontal cortex (DLPFC) in Class III and Class I/II patients (whole brain cluster corrected (WBCC), p < 0.05), which was significantly higher in Class III vs. Class I/II (p < 0.05). We found decreased activation in the insula in the fasted state, which was significantly lower in Class I/II vs. Class III (p = 0.03). In the fed state, we found increased activation in the DLPFC in Class III and Class I/II (WBCC, p < 0.05). The increased activation in cognitive control/inhibition regions (DLPFC) is consistent with the summative literature; however, the decreased activation in taste information processing regions (insula) was unexpected.ConclusionsOur results provide novel insights on food cue response between different classes of obesity and highlight the importance of targeting the DLPFC in weight loss interventions, particularly in severely obese patients. Additional studies examining food-related neural circuitry between different classes of obesity are needed.

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha.

Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.

Role of insulin-like growth factors family in endometrial cancer

The expression and activity of insulin-like growth factors (IGFs) are increased in endometrial cancer (EC). IGFs not only mediate the positive impact of estrogen on EC, but also increase the risk for development of EC in patients with metabolic disorder. In addition, IGFs play a key role in the invasion, metastasis and drug resistance of EC. Thus, drugs that target IGFs may be the novel treatment of EC. Key words: Endometrial neoplasms; Insulin-like growth factors

Adiponectin and Endometrial Cancer: A Systematic Review and Meta-Analysis

Objective: This study evaluates the association between serum adiponectin concentrations and the risk of endometrial cancer through a comprehensive meta-analysis of currently available clinical data. Methods: PubMed, Embase, the Chinese Biomedical Literature Database and the Science Citation Index (ISI Web of Science) were searched for studies that examined the association between blood adiponectin concentrations and the risk of endometrial cancer. Data from studies that met the inclusion criteria were systematically reviewed, and pooled analyses were performed according to the guidelines of Meta-Analysis of Observational Studies in Epidemiology and PRIMSA. Results: Eight case-control studies (including 1257 endometrial cancer patients and 2008 controls) and four nested case-control studies (including 659 endometrial cancer patients and 1398 controls) were included. We found that serum adiponectin level was inversely correlated with the risk of endometrial cancer development after pooling the case-control studies (OR = 0.50, 95% CI: 0.39-0.60; P < 0.001). However, meta-analysis of nested case-control studies thus far did not support a broad linkage between serum adiponectin level and endometrial cancer, although a correlation may exist in the subgroup of postmenopausal women (OR=0.81, 95%CI: 0.65-1.00; P=0.060), particularly in postmenopausal women without current hormone replacement therapy (OR = 0.62, 95% CI: 0.44-0.86; P = 0.004). Conclusions: Meta-analysis of currently available clinical evidence supports the association between high serum adiponectin concentration and reduced risk of endometrial cancer development, particularly in the group of postmenopausal women without current hormone replacement therapy. However, additional studies with prospective design are required to fully support this linkage.

Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development

Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.

Expression of thyroid transcription factor-1 in normal endometrium is associated with risk of endometrial cancer development

AbstractThyroid transcription factor-1 (TTF-1) is a DNA-binding protein that is mainly expressed in thyroid and lung tissue, but has also been found in gynecologic tissue. Recent studies have suggested that TTF-1 has tumor suppressor function in lung adenocarcinoma models. In the current study, we examined whether expression of TTF-1 in benign endometrium and endometrial hyperplasia might impact on the risk of developing endometrial cancer. Formalin-fixed paraffin-embedded endometrial tissues obtained from 535 cases were used to construct an endometrial tissue microarray. One hundred fifty of 207 patients had multiple serial endometrial specimens including 46 patients who progressed to endometrial cancer. The tissue microarray included a range of histopathologies including benign endometrium (n=231), simple hyperplasia (n=105), complex hyperplasia (n=36), simple atypical hyperplasia (n=10), complex atypical hyperplasia (n=44), and endometrial carcinoma (n=109). Expression of TTF-1 by immunohistochemistry in benign endometrium and endometrial hyperplasia was correlated with progression to cancer and clinical features known to be associated with increased risk of developing endometrial cancer. Carcinoma specimens showed a significantly greater expression of TTF-1 compared with benign endometrium and non-atypical hyperplasia (P=0.0007 and P=0.05). Presence of TTF-1 expression in benign endometrium was associated with a significantly decreased risk of cancer development (P=0.003, hazards ratio=0.104, 95% CI: 0.024–0.455). TTF-1 expression in hyperplasia did not significantly correlate with progression to cancer. The data from our study show that TTF-1 expression in normal endometrium is associated with a reduced risk of endometrial cancer development. This observation suggests that TTF-1 might function as a tumor suppressor in endometrial tissue. TTF-1 expression in normal endometrium could potentially provide clinically useful information as a biomarker for the risk of endometrial cancer.

Abstract A16: Longitudinal evaluation of cancer-associated biomarkers before and after weight loss: Implications for cancer risk reduction

Abstract Introduction: Obesity is a major risk factor for the development of endometrial cancer (EC). An improved understanding of biologic mechanisms associated with weight loss may guide preventive strategies for EC development. The goal of this study was to explore longitudinal biomarker changes in obese women who lost weight by participating in the Re-Energize with Nutrition, Exercise and Weight Loss (RENEW) study. We hypothesized that intentional weight loss may reduce EC risk through modification of biomarkers related to inflammation, hormonal balance, and cancer antigens. Methods: Serum samples from 89 participants with Class II and Class III obesity (mean body mass index (BMI) = 43.84 ± 5.4 kg/m2, total body fat = 58.5 ± 10.4%) were obtained in the RENEW study. Samples were also obtained from a comparison group of 43 controls representing lean, overweight, and class I obese subjects, measured once at baseline. Twenty-one bead-based xMAP immunoassays were utilized in this study: cancer-associated antigens 125 and 15-3, carcinoembryonic antigen (CEA), interleukins (IL) 2, 6, 7, 8, 10, IL-receptor 1alpha, tumor necrosis factor alpha (TNF-a), insulin-like growth factor binding proteins (IGFBP) 1 and 2, vascular endothelial growth factor (VEGF), eotaxin, soluble E-selectin, thyroid stimulating hormone (TSH), prolactin, growth hormone (GH), resistin, adiponectin, and insulin like growth factor 1 (IGF-1). Biomarker expression was analyzed at the Luminex Core Facility at the University of Pittsburgh Cancer Institute. Linear regression was used to evaluate the association between baseline BMI and biomarker expression adjusted for age, race, and smoking status. A one-way repeated measures analysis of variance was used to examine the association between changes in biomarker expression levels over time (baseline, 6 months and 12 months). Linear mixed effects models were used to examine longitudinal relationships between biomarker expression levels, BMI, steps, and time period adjusting for age, race, and smoking status. Results: Participants in the RENEW study lost an average of 12.8 kg from baseline to the 12 month assessment, with the largest change occurring in the first 6 months of the intervention. Mean levels of VEGF, soluble E-selectin, GH, adiponectin, IL-6, IL-7, CA-125, and IGFBP-1 significantly differed between time periods. In adjusted mixed linear models, decreasing BMI was significantly associated with decreased in soluble E-selectin and IL-6 and increases in GH, adiponectin, and IGFBP-1. Conclusions: This is one of the first efforts to explore changes in cancer-associated biomarkers in a cohort of weight loss research participants at high risk for EC development. This work adds to the current literature in several fields including endometrial cancer biomarkers, physical activity, and weight loss, and has significant potential implications for EC prevention. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A16.

Serum leptin–adiponectin ratio and endometrial cancer risk in postmenopausal female subjects

Objective Obesity is a well-known risk factor for the development of endometrial cancer. Elevated endogenous estrogen and insulin resistance are recognized to be major factors that link obesity and cancer development. However, there is increasing evidence that the adipokines adiponectin and leptin, which are directly produced in adipose tissue, impact several obesity-related cancers. The purpose of the current study was to investigate the relationships of the concentration of leptin, adiponectin, and the leptin-to-adiponectin ratio (L/A ratio) with the endometrial cancer risk in postmenopausal female subjects. Methods A case-control study was performed in 146 postmenopausal female subjects with endometrial cancer and 150 control subjects with no history of cancer. The serum levels of the adipokines leptin and adiponectin were measured, and the associations of these adipokines and the L/A ratios with the endometrial cancer risk were analyzed. Results The leptin levels and the L/A ratios were significantly higher in the incident cases of endometrial cancer (8.2 ± 0.5, 2.05 ± 1.08 ng/ml) than in the controls subjects (4.5 ± 0.5, 0.98 ± 0.18, P < 0.0001), whereas the adiponectin levels were significantly lower in the incident cases (6.2 ± 0.4 μg/ml) than in the control subjects (9.0 ± 0.4 μg/ml, P < 0.0001). For the incident cases, the serum levels of the adipokines were significantly correlated with the patient body mass index (BMI) (P < 0.001 for leptin, P < 0.05 for adiponectin), and the leptin levels and the L/A ratios were significantly correlated with the homeostasis model assessment ratio (HOMA-R) and the fasting insulin levels (P<.001). Higher L/A ratios were found to be significantly associated with an increased risk of endometrial cancer [OR (95% CI) for the top vs. the bottom tertile of the L/A ratio was 6.0 (3.2–11.9), P-value < 0.0001]. Moreover, the ORs of the L/A ratios were higher than those of leptin or adiponectin alone. The association of the L/A ratios with endometrial cancer risk remained after adjusting for the obesity indices, hypertension, and presence of diabetes mellitus. Conclusion The present results suggested that the L/A ratio was independently associated with an increased risk for endometrial cancer development. Additional research will elucidate the molecular mechanisms by which these adipokines are associated with the development of endometrial cancer.

Abstract 922: Association of the hSRBC gene polymorphism with endometrial cancer

Abstract Background: hSRBC is a putative tumor suppressor located at 11p15.4, at which frequent genomic loss has been observed in several human malignancies. We previously reported that hSRBC expression is frequently downregulated in many types of human cancers due to aberrant promoter CpG sites hypermethylation, and hSRBC activation induces cell cycle arrest and apoptosis by enhancing the protein stability of p53. Interestingly, our recent studies suggest that hSRBC might be a novel transcription target of TNFα, which plays a crucial role in inflammation and tumorigenesis. We explored the possible association of an intreaexonic SNP (T509C), which results in a Leu to Pro substitution, with risk for endometrial cancer development. Methods: TNFα regulation of hSRBC expression was examined using semi-quantitative RT-PCR and immunoblot assays. Endometrial tissues from 147 cancer patients and 191 healthy individuals were included for test for SNP T509C by restriction endonuclease PvuII-based genotyping. Allele frequencies in cancer specimens were compared with those in healthy controls. Results: Allelic frequencies of T and C at the T509C position was 30.27% and 69.73% in healthy control and 37.17% and 62.83% in cancer specimens, respectively. Allelic frequency at T509C in cancer specimens showed no significant difference compared to controls. However, genotype frequencies of TT, CT, and CC in healthy controls were 16.75%, 40.84%, and 42.412%, respectively, while cancer specimens displayed 14.97%, 30.61%, and 54.42%. The CC genotype frequency in cancer specimens was significantly higher (p &amp;lt; 0.05) compared with that in healthy controls. Conclusion: Although the number of specimens used in this study is not enough, this study raises the possibility that the T509C SNP of hSRBC, a putative novel transcription target of TNFα and proapoptotic tumor suppressor, might be associated with endometrial cancer development. Further genotype screening of several other SNPs within hSRBC in cancer patients would provide valuable diagnostic and prognostic information for human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 922.

Progesterone receptor (PROGINS) polymorphism and the risk of endometrial cancer development

The progesterone receptor gene (PROGINS) has been identified as a risk modifier for benign and malignant gynecological diseases. The present case-control study is to evaluate the role of the PROGINS polymorphisms, as risk factor, for endometrial cancer development and to investigate the association between these genetics variants and clinical/pathologic variables of endometrial cancer. PROGINS polymorphism was examined in a total of 121 patients with endometrial cancer and 282 population-based control subjects, all located at the same area in São Paulo, SP, Brazil. The genotyping of PROGINS polymorphism was determined by polymerase chain reaction. The frequencies of PROGINS polymorphism T1/T1, T1/T2, and T2/T2 were 82.6%, 14.9%, and 2.5% in the endometrial cancer patients and 78.4%, 21.6%, and 0% in the controls, respectively. The chi(2) test showed a higher incidence of the T2/T2 genotype in the endometrial cancer group subjects, these results were statistically different (P= 0.012). However, due to the fact that there were no women in the control group showing homozygosis for the allele T2, the correct evaluation of odds ratio could not be properly calculated. Regarding the clinical and pathologic findings observed within the group of patients with endometrial cancer, there was significant correlation between T1/T2 genotype and the presence of myoma (P= 0.048). No correlations were observed among the other variables. These data suggest that the PROGINS polymorphism T2/T2 genotype might be associated with an increased risk of endometrial cancer.

Suppression of Estrogenic Activity by Medroxyprogesterone Acetate in Tamoxifen-treated Patients after Surgery for Breast Cancer to Reduce the Risk of Endometrial Cancer Development.

BACKGROUND: Postoperative adjuvant tamoxifen (TAM) therapy in breast cancer patients may lead, albeit rarely, to endometrial cancer. Preventive measures are urgently needed. METHODS: The study subjects were postmenopausal women who had undergone surgery for breast cancer. The control group (n=10) received no further therapy. Patients who had completed adjuvant TAM therapy were assigned to a medroxyprogesterone acetate (MPA;400 mg/day orally for 4 weeks) group (n =15) or no MPA treatment group (no MPA group)(n=15). Uterine cervix cytodiagnosis was performed after completing the TAM therapy(initial), and 4(4-week)and 16(16-week)weeks later. The serum 17beta-estradiol (E2) and progesterone concentrations were measured initially and at 4 weeks. The karyopyknotic index (KPI), eosinophilic index (EI) and maturation index (MI) were calculated from Papanicolaou-stained specimens. RESULTS: The background parameters showed no biases. There were no differences in the PKI or El between the no MPA and MPA groups. However, regarding the MI, after 4 weeks in the MPA group, the intermediate cells were significantly increased, while the superficial cells tended to be significantly decreased. Regarding the percent change from the initial value, after 4 weeks in the MPA group, the KPI and superficial cells were significantly decreased, and the intermediate cells were significantly increased. The estrogen activity level and the progesterone concentration were significantly lower in the MPA group compared with the no MPA group. CONCKLUSIONS: The MPA administration clearly lowered the estrogenic activity, indicating that MPA therapy should be effective in reducing the risk of TAM-associated endometrial cancer.