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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this paper is to report the risk of development of gynecological cancer in women receiving hormone replacement therapy and to review the current knowledge on the administration of hormone replacement therapy following treatment of gynecological cancer. Estrogens alone may act as promoting factors for endometrial carcinogenesis. However, the addition of progestins reduces the risk of endometrial cancer to that of nonusers. Hormone replacement therapy could be given to selected patients following treatment for endometrial cancer. However, we think that this therapy should be reserved only for patients enrolled in controlled clinical trials. Ovarian cancer does not seem to be sensitive to estrogens, even if current literature does not allow firm conclusions to be drawn. Hormone replacement therapy should be offered to patients previously treated for ovarian cancer and cervical cancer.
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PMID:Hormone replacement therapy and gynecological cancer. 942 82

We describe here a case-control study to identify associations between polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) and cytochrome P-450 1A1 (CYP1A1) genes and susceptibility to endometrial cancer. Accordingly, genotype frequencies in 80 endometrial carcinoma patients were compared with frequencies in 60 controls. DNA analysis suggest a significantly increased endometrial cancer risk with an alanine to valine substitution at nucleotide 677 of MTHFR gene with an odds ratio of 2.8 (95% confidence interval: 1.36-6.14, P = 0.002). Moreover, the tumors from patients with the valine allele were more undifferentiated (P = 0.03). On the other hand, a recently described mutation in exon 7 of CYP1A1 gene (threonine exchanged to asparagine in codon 461) showed a strong association with endometrial cancer risk with an odds ratio of 6.36 (95% confidence interval: 1.99-26.5, P = 0.0004). Thus, this study suggests that polymorphisms at MTHFR and a novel CYP1A1 variant could influence susceptibility to endometrial cancer, although larger sample sizes would be required to corroborate these findings.
Carcinogenesis 1997 Dec
PMID:Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility. 945 Apr 74

Clinicopathological, immunohistochemical and molecular genetic analyses of endometrial carcinoma suggest different pathogenetic pathways for endometrioid and serous carcinoma. Most endometrioid carcinomas are associated with endometrial hyperplasia, are ER/PR positive, p53 negative and express low Ki-67. In contrast, almost all serous carcinomas develop from endometrial intraepithelial carcinoma (EIC) in a background of atrophy. These tumors are ER/PR negative, strongly express p53 and show high Ki-67 labeling. On the molecular genetic level, 25-30% of endometrioid carcinomas show microsatellite instability (MI), 25-30% harbor mutant K-ras and less than 10% have mutant p53. In contrast, more than 90% of serous carcinomas have p53 mutations, 2% K-ras mutations and none MI. Among endometrioid carcinomas, K-ras mutations occur most frequently in FIGO grade 2 and 3 tumors and p53 mutations in FIGO grade 3 tumors. In contrast, MI is equally distributed among all FIGO grades. These findings support the view that endometrioid carcinoma develops slowly in a progressive fashion from endometrial hyperplasia. Mutation of p53 occurs late in tumor progression. Thus, endometrioid carcinogenesis resembles the proposed model for colorectal carcinogenesis. In contrast, serous carcinoma develops rapidly from EIC in a background of atrophy. Mutation of p53 occurs early in serous carcinogenesis and this may account for the highly aggressive behavior of this tumor.
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PMID:A dualistic model for endometrial carcinogenesis based on immunohistochemical and molecular genetic analyses. 947 74

Hereditary nonpolyposis colorectal cancer (HNPCC), also termed Lynch syndrome, was originally called cancer family syndrome. Historically, in 1913 Aldred Warthin, a pathologist, published a family, now known as Family G, which had features of HNPCC. It was first delineated as a hereditary cancer syndrome in the mid-1960s by Lynch. There was an apparent autosomal dominant mode of inheritance of colorectal cancer and certain integral cancers, the most prominent of which was endometrial carcinoma. Prior to the discovery in 1993 and 1994 of genes (hMSH2, hMLH1, hPMS1, hPMS2) known as mis-match repair genes or mutator genes, the diagnosis of HNPCC rested exclusively upon evaluation of clinical findings in concert with a well-documented and extended pedigree. Thus, this disorder has evolved from a medical curiosity into a clinical syndrome wherein molecular biologists provided proof of its hereditary status. These discoveries should aid in elucidating its pathogenesis and carcinogenesis and in the next decade we likely will learn more about chemoprevention and surgical prophylaxis of HNPCC.
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PMID:Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation. 949 83

Endometrial carcinoma shows various histological types that differ in their clinical presentation and prognosis. Comparative genomic hybridization was used to detect gains and losses of DNA sequences along all chromosome arms in 24 uterine serous and 24 uterine endometrioid carcinomas. In serous carcinomas, extensive genetic aberrations were detected in 17 of the 24 specimens, with a mean of 5.7 changes per tumor. The most frequent gains occurred at 3q (50%), 8q (33%), 5p (29%), 6p (29%), and 1q (29%), and the most common losses were located at 4q (17%), 15q (17%), and 18q (17%). Tumors exhibiting DNA copy number changes were associated with shorter overall survival. In endometrioid carcinomas, genetic aberrations were less frequent and simpler than in serous carcinomas. DNA sequence copy number changes were observed in 12 of the 24 cases, with a mean of 1.5 changes per tumor. The most frequent aberrations were gains at 1q (29%), 2q (13%), and 8q (13%). Losses were rarely observed. The diverging pattern of genetic changes observed in uterine serous and endometrioid carcinomas suggests different pathways of carcinogenesis in these tumor types.
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PMID:Distinct chromosomal imbalances in uterine serous and endometrioid carcinomas. 950 Apr 45

Bcl-2 protein inhibits apoptosis, reduces the requirement for growth factors, and thereby extends the survival of cells. Recent findings of Bcl-2 in several solid tumors suggest that it might contribute to the genesis of some types of cancer. Over-expression of Bcl-2 might play a role in carcinogenesis and malignant progression of endometrial carcinoma. The aims of this study were to determine Bcl-2 expression in endometrial carcinoma in relation to other histopathologic prognostic factors, and to test its prognostic significance in patients with endometrial carcinoma. A total of 61 endometrioid-type endometrial carcinomas were immunohistochemically investigated for Bcl-2 expression on cryostat sections. Bcl-2 localization was observed in cytoplasm in 18 tumors, in nucleus in 27 tumors, or in both in 5 tumors. In 11 tumors, Bcl-2 was observed neither in cytoplasm nor in nucleus. There was not a statistically significant relationship between grade of tumor and Bcl-2 expression. Cytoplasmic Bcl-2 became less frequently expressed as the tumor invaded the myometrium deeper (p < 0.025). Retroperitoneal lymph-node dissection was performed in 57 patients. Multiple-regression analysis showed that lymph-vascular space invasion and nuclear expression of Bcl-2 were correlated to pelvic lymph-node metastasis (p < 0.0001 and < 0.05 respectively). Univariate Cox regression analysis revealed that nuclear Bcl-2 expression was associated with shorter survival (p < 0.05) than that of patients with cytoplasmic Bcl-2 expression. Pelvic node metastasis was a significant prognostic factor for patients who underwent systematic retroperitoneal lymph-node dissection. Cox multivariate-regression analysis revealed that pelvic node metastasis and cervical invasion were the most important prognostic factors in this series of patients. When the analysis was made after exclusion of pelvic node metastasis, histologic grade (hazard ratio = 2.4), cervical invasion (hazard ratio = 3.7) and nuclear Bcl-2 expression (hazard ratio = 11.5) were shown to be significant predictors of survival of the patients. These results indicate that aberrant Bcl-2 expression might be involved in malignant progression of endometrioid-type endometrial carcinoma. Site of Bcl-2 localization may be an important predictor of prognosis for patients with endometrioid-type endometrial carcinoma.
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PMID:Bcl-2 expression and prognosis of patients with endometrial carcinoma. 958 30

Although combined hormone replacement therapy using estrogens and progestins reduces the risk of endometrial cancer in postmenopausal women, it has been unclear whether the combined therapy is associated with an alteration of the risk of mammary cancer. Virgin mice of the SHN strain, which has a high potential for the development of mammary cancer and uterine adenomyosis, were given diets containing conjugated estrogens with or without medroxyprogesterone acetate for 230 days. The combined administration of conjugated estrogens and medroxyprogesterone acetate completely suppressed the development of uterine adenomyosis with a decrease in uterine thymidylate synthetase activity, significantly enhanced the bone mineral density in the femur and slightly shortened the latent period of mammary carcinogenesis.
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PMID:Effects of conjugated estrogens with or without medroxyprogesterone acetate on mammary carcinogenesis, uterine adenomyosis and femur in mice. 960 4

Forty years ago, Lerner and coworkers (1958) discovered the first nonsteroidal antiestrogen and Jensen (Jensen and Jacobson, 1960) identified a target for drug action, the ER. This knowledge opened the door for the clinical development of tamoxifen which we now know provides a survival advantage in both node-positive and node-negative patients with ER-positive disease (Early Breast Cancer Trialists Collaborative Group, 1992, 1998). The drug has been studied extensively, and the results have provided an invaluable insight into possible ancillary advantages of "antiestrogens", i.e., maintenance of bone density and the prevention of coronary heart disease, and possible disadvantages, i.e., rat liver carcinogenesis and an increased risk of endometrial cancer. Most importantly, the identification of the target site-specific actions of tamoxifen caused a paradigm shift in the prospective uses of antiestrogens from a direct exploitation of the antitumor properties to the broader application as a preventative for osteoporosis, but with the beneficial side effects of preventing breast and endometrial cancer. Raloxifene, a second-generation SERM, has all the properties in the laboratory that would encourage development as a safe preventative for osteoporosis (Jordan et al., 1997). As a result, raloxifene has been evaluated in more than 11,000 postmenopausal women and found to maintain bone density with significant decreases in breast cancer incidence and no increase in endometrial thickness. Raloxifene is now available as a preventative for osteoporosis in postmenopausal women. There is every reason to believe that a multifaceted agent like raloxifene will find widespread use, and there will be continuing interest by the pharmaceutical industry in the development of new agents with even broader applications. The extensive clinical effort is augmented by past molecular innovations in the laboratory and the future promise of new discoveries. The cloning and sequencing of the ER (Green et al., 1986; Greene et al., 1986) has allowed the development of an ER knock-out mouse (Lubahn et al., 1993) that compliments Jensen's pioneering work (Jensen and Jacobson, 1962) and describes the consequences of the loss of ER alpha. However, ER beta (Kuiper et al., 1996), the second ER, has provided an additional dimension to the description of estrogen and antiestrogen action. For the future, the development of ER beta monoclonal antibodies, the classification of target sites for the protein around the body, and the creation of ER beta and ER alpha, beta knock-out mice will identify new therapeutic targets to modulate physiological functions. Clearly, the successful crystallization of ER alpha with raloxifene (Brzozowski et al., 1997) must act as a stimulus for the crystallization of ER beta. The central issue for research on antiestrogen pharmacology is the discovery of the mechanism (or mechanisms) of target site-specificity for the modulation of estrogenic and antiestrogenic response. The description of a stimulatory pathway for antiestrogens through an AP-1 ER beta signal transduction pathway (Paech et al., 1997), although interesting, may not entirely explain the estrogenicity of antiestrogens. The model must encompass the sum of pharmacological consequences of signal transduction through ER alpha and ER beta with the simultaneous competition from endogenous estrogens at both sites. This is complicated because estradiol is an antagonist at ER beta through AP-1 sites (Paech et al., 1997), so this is clearly not the pathway for estrogen-induced bone maintenance in women. Estrogen is stimulatory through ER alpha, but antiestrogens are usually partial agonists and may either block or stimulate genes. However, we suggest that the ER alpha stimulatory pathway could be amplified through selective increases in coactivators. The principle is illustrated with the MDA-MB-231 cells stably transfected with the cDNAs for the wild-type and the amino acid 351 mutan
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PMID:Basic guide to the mechanisms of antiestrogen action. 964 65

Tamoxifen increases the risk of human endometrial cancer and is a potent carcinogen in rat liver, in which it produces DNA adducts and cytogenetic damage. Nevertheless its prophylactic use against breast cancer in healthy women is under investigation in several large trials. To investigate whether rat hepatocarcinogenicity predicts human hepatocarcinogenicity we used genetically engineered bacterial and mammalian target cells to investigate how alpha-hydroxy-tamoxifen, a major phase I metabolite of tamoxifen, is further metabolised by rat and human phase II enzymes, sulfotransferases, to mutagenic and DNA-adduct-forming species. We expressed rat hydroxysteroid sulfotransferase a, a liver-specific enzyme, and corresponding human sulfotransferase in bacteria (Salmonella typhimurium) and in a mammalian cell line (Chinese hamster V79 cells) and tested alpha-hydroxytamoxifen for DNA adduct formation and mutagenicity in these systems, using unmodified cells as controls. In cells that expressed rat hydroxysteroid sulfotransferase, alpha-hydroxytamoxifen was mutagenic and formed the same pattern of DNA adducts as that found in the liver of tamoxifen-treated rats. Alpha-hydroxytamoxifen was not activated, or was at least 20 times less active in cells expressing human hydroxysteroid sulfotransferase. All the other six known human xenobiotic-metabolising sulfotransferases were also expressed in S. typhimurium. None activated alpha-hydroxytamoxifen to a mutagen. These results suggest that the risk of DNA adduct formation, and cancer, in the human liver is low and explain why tamoxifen is a powerful carcinogen to the rat liver, and why standard short-term tests fail to detect its mutagenicity.
Carcinogenesis 1998 Oct
PMID:Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. 980 49

Carcinoma of the uterine cervix is a common malignancy among women that has been found to show loss of heterozygosity in the chromosome 11p. Recent studies have localized the TSG101 gene in this region, and also demonstrated a high frequency of abnormalities of this gene in human breast cancer. To determine the role of the TSG101 gene in the carcinogenesis of cervical and uterine carcinoma, 19 cases of cervical carcinoma and five cases of endometrial carcinoma, as well as nearby non-cancerous tissue from the same patients, and 16 blood samples from healthy persons as normal control were analysed by Southern blot analysis of genomic DNA, reverse transcription of the TSG101 mRNA followed by PCR amplification and sequencing of the products. We found that abnormal transcripts of the TSG101 gene were common both in cancerous or non-cancerous tissues of the uterus and cervix and in normal peripheral mononuclear cells. There was no genomic deletion or rearrangement in spite of the presence of abnormal transcripts, and no definite relationship between the abnormal transcripts and HPV infection was found. Although the frequency of abnormal transcripts was higher in cancerous than in non-cancerous tissue, normal peripheral mononuclear cells also had abnormal transcripts. Given these findings, the role of the TSG101 gene as a tumour-suppressor gene should be re-evaluated. Because some aberrant transcripts could be found at the first PCR reaction, we suggest that the aberrant transcripts might be the result of imperfect minor splicesome products.
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PMID:Analysis of TSG101 tumour susceptibility gene transcripts in cervical and endometrial cancers. 1002 11


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