Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was aimed at comparing the effect of clinical staging and radiotherapy on natural killer (NK) and interferon-activated killer (IAK) cell activity in a group of endometrial cancer patients receiving a total dose of 5,000 to 8,000 rads. We report that when compared to age-matched women, a significantly higher number and percentage of patients show low NK and IAK cell activity. At diagnosis, diminished NK activity was seen in about 20% of the patients, while IAK activity was low in 49% of these patients. There was no correlation between these deficiencies and the grade or stage of the disease. In contrast, radiotherapy induced deleterious effects on both populations of NK and IAK cells. These deleterious effects were more pronounced in patients showing a low level of spontaneous NK activity. In an attempt to understand better the mechanism by which the presence of cancer itself and/or radiotherapy affects these activities, we studied in greater detail changes in peripheral blood T-cell numbers and subsets. Before radiotherapy, all lymphocyte counts were within the normal range. In contrast, after radiotherapy the absolute numbers of all T-cell subsets were significantly decreased in the majority of the patients tested, OKT4+ cells being the most radiosensitive and Leu 7+ cells the most radioresistant.
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PMID:Early inhibition of natural and interferon-activated killers in endometrial cancer patients treated with local radiotherapy. 243 75

Effect of mAb against the CD11a-c, CD18, and GP84 adhesion molecules on the binding and cytotoxicity of human NK cells was studied. The target cells were K562, MOLT-4, Raji, and fresh uncultured autologous endometrial carcinoma cells. Antibodies against adhesion relevant epitopes of CD11a(TA-1/LFA-1), CD11b(Mol/OKM1/Mac1), or CD11c (Leu-M5) did not inhibit NK function. The mAb 60.3 against CD18, the common beta-chain associated to CD11a-c, strongly inhibited both the binding and cytotoxicity of large granular lymphocytes (LGL) against all the target cells tested. Also the antibody LB-2 against the GP84 adhesion molecule inhibited NK function to some degree. 60.3 and LB-2 antibodies exerted an additive effect in the inhibition of both binding and cytotoxicity. However, even this antibody combination did not completely block NK activity, suggesting a heterogeneity of adhesion structures in the NK system. According to both FACS analyses and immunoprecipitation studies, all the tested antibodies recognized either a subpopulation or all of LGL. On the other hand, antibodies against CD11b, CD11c, and LB-2 showed only marginal reactivity with highly purified LGL-free T cells.
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PMID:CD11a-c/CD18 and GP84 (LB-2) adhesion molecules on human large granular lymphocytes and their participation in natural killing. 289 96

Sixteen cases of small-cell carcinoma of the endometrium were encountered in patients who ranged in age from 30 to 78 (mean, 57.4) years. Of the 12 patients whose presenting features are known, eight had abnormal vaginal bleeding, three had pain related to metastatic tumor, and one patient had both symptoms. On pelvic examination, adnexal masses were palpable in three patients, and vaginal involvement was evident in two; one patient had a large palpable periumbilical mass. Thirteen patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Extrauterine spread was documented intraoperatively in eight cases, including widespread intraabdominal and ovarian metastases in four cases, vaginal involvement in the two cases noted previously, paraaortic lymph node involvement in one case, and tubal involvement in one case. Three tumors were International Federation of Gynecology and Obstetrics (FIGO) stage I, four were stage II, two were stage III, and six were stage IV; in one case, there was insufficient information to allow staging. On gross examination, the tumors were usually described as bulky, ill-defined, and invasive of the myometrium; four were polypoid. Microscopic examination revealed sheets, cords, and nests of small or intermediate-sized cells with scanty cytoplasm, hyperchromatic nuclei, and a high mitotic rate. Single-cell and zonal necrosis and vascular invasion were typically present. Synchronous grade 1 or grade 2 endometrial endometrioid adenocarcinoma was present in eight cases, and complex atypical endometrial hyperplasia, in two others. In three cases, the adenocarcinoma merged almost imperceptibly with the small-cell component. None of the tumors contained argyrophil or argentaffin cells, although nine of 11 tumors were immunoreactive for neuron-specific enolase (one of these was also Leu-7 positive), and another was chromogranin positive. Of the 11 cases with follow-up information, seven patients died of disease (at least four with distant metastases) with a median survival of 12 months, and another patient was alive with distant metastases at 18 months. The remaining patients were clinically free of disease at postoperative intervals of < or = 1 year (two cases) and 4.5 years (one case). This study confirms that small-cell carcinomas of the endometrium are a histologically distinctive subtype of endometrial carcinoma, which, like their counterparts in the uterine cervix, are aggressive tumors with a propensity for systemic spread and a poor prognosis.
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PMID:Small-cell carcinoma of the endometrium. A clinicopathological study of sixteen cases. 751 54

We screened for germline mutations of mismatch repair genes, hMLH1 and hMSH2, in five Japanese families carrying hereditary nonpolyposis colorectal cancer (HNPCC) and in a patient with multiple primary cancers. Screening the entire coding regions of both genes using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis, we found two novel germline mutations in hMSH2. One was a 1-bp insertion in exon 12, detected in a patient who had undergone surgery six times for independent tumors (four primary colorectal carcinomas, a small intestinal carcinoma, and an endometrial cancer). The other, in a second patient, was a missense mutation from CTT to TTT at codon 390 in exon 7 that resulted in substitution of phenylalanine for leucine. This conservative alteration was not found in any of 50 normal controls, but we cannot exclude the possibility that it may represent a rare polymorphism rather than a factor in the disease.
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PMID:Novel germline mutations of hMSH2 in a patient with hereditary nonpolyposis colorectal cancer (HNPCC) and in a patient with six primary cancers. 962 22

Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI-1544, and MI-1892 through lysyl side chains and a tetrapeptide spacer, Gly-Phe-Leu-Gly (X) to a copolymer, poly(N-vinylpyrrolidone-co-maleic acid) (P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast cancer cells in immunodeficient mice. MCF-7 cells treated with P-X-1544 and P-X-1892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at lower doses and in the G1 and G2 phases after 48 h. Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for direct antiproliferative effects on the cancer cells but not for interactions in the pituitary indicates the therapeutic potential of the conjugates.
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PMID:Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity. 1005 47

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG-->ATA, Met-->Ile) and 2) a missense mutation at codon 390 (CTT-->TTT, Leu-->Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled.
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PMID:Identification of germline MSH2 gene mutations in endometrial cancer not fulfilling the new clinical criteria for hereditary nonpolyposis colorectal cancer. 1449 97

Allelic variations in CYP1B1 are reported to modulate the incidence of several types of cancer. To provide a mechanistic basis for this association, we investigated the impact of nonsilent allelic changes on the intracellular levels and post-translational regulation of CYP1B1 protein. When transiently expressed in COS-1 cells, either in the presence or absence of recombinant cytochrome P450 reductase, the cellular level of the CYP1B1.4 allelic variant (containing a Ser at the amino acid position 453; Ser453) was 2-fold lower compared with the other four allelic CYP1B1 proteins (containing Asn453), as analyzed by both immunoblotting and ethoxyresorufin O-deethylase activity. This difference was caused by post-translational regulation; as in the presence of cycloheximide, the rate of degradation of immunodetectable and enzymatically active CYP1B1.4 was distinctly faster than that of CYP1B1.1. Pulse-chase analysis revealed that the half-life of CYP1B1.4 was a mere 1.6 h compared with 4.8 h for CYP1B1.1. The presence of the proteasome inhibitor MG132 [N-benzoyloxycarbonyl (Z)-Leu-Leuleucinal] increased the stability not only of immunodetectable CYP1B1, but also--unexpectedly given the size of the proteasome access channel--increased the stability of enzymatically active CYP1B1. The data presented herein also demonstrate that CYP1B1 is targeted for its polymorphism-dependent degradation by polyubiquitination but not phosphorylation. Our results importantly provide a mechanism to explain the recently reported lower incidence of endometrial cancer in individuals carrying the CYP1B1*4 compared with the CYP1B1*1 haplo-type. In addition, the mechanistic paradigms revealed herein may explain the strong overexpression of CYP1B1 in tumors compared with nondiseased tissues.
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PMID:Proteasomal degradation of human CYP1B1: effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression. 1548 49

2-Hydroxylated metabolites of estrogen have been shown to have antiangiogenic effects and inhibit tumor cell proliferation, whereas 4-hydroxylated metabolites have been implicated in carcinogenesis. We examined whether polymorphisms in certain genes involved in estrogen metabolism are associated with endometrial cancer risk in a population-based case-control study with 371 cases and 420 controls. Based on previously published genotype-phenotype correlation studies, we defined variant alleles thought to increase estrogen 2-hydroxylation as presumptively low-risk (CYP1A1 m1 T6235C and m2 Ile(462)Val) and those thought to increase estrogen 4-hydroxylation as high-risk (CYP1A1 m4 Thr(461)Asn, CYP1A2 A734C, and CYP1B1 Leu(432)Val). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. Carrying at least one CYP1A1 m1 or m2 variant allele was associated with a decreased risk of endometrial cancer [ORs (95% CIs), 0.64 (0.44-0.93) and 0.54 (0.30-0.99), respectively]. No strong alteration in risk was observed among women with any of the putative high-risk alleles. When CYP1A1, CYP1A2, and CYP1B1 genotypes were combined and ranked by the number of putative low-risk genotypes carried, women with four or five low-risk genotypes had a reduced risk of endometrial cancer (OR, 0.29; 95% CI, 0.15-0.56) compared with women with one or none. No appreciable alteration in risk was observed among women carrying two or three low-risk genotypes. Some of our findings are consistent with the hypothesis that increased estrogen 2-hydroxylation is associated with decreased endometrial cancer risk, but replication of these results is required before any firm conclusions can be reached.
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PMID:Genetic factors in catechol estrogen metabolism in relation to the risk of endometrial cancer. 1573 58

Cigarette smoking is inversely associated with endometrial cancer risk. Smoking is proposed to decrease risk, in large part, through its anti-estrogenic effects in the uterus. In addition, cigarette smoke is a major source of alkylation damage. The O6-methylguanine DNA methyltransferase (MGMT) gene is responsible for repairing alkylation DNA damage and also has a role in inhibiting estrogen receptor-mediated cell proliferation. Because of MGMT's dual functions, it is a strong candidate gene for endometrial cancer. We assessed the two functional polymorphisms, the Leu84Phe and Ile143Val, in relation to endometrial cancer risk in a nested case-control study within the Nurses' Health Study (cases = 456, controls = 1134). Compared with the 84Leu/Leu genotype, the Phe carriers had a significantly decreased risk of endometrial cancer [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.53-0.96]. We did not observe an association between the Ile143Val polymorphism and endometrial cancer risk overall. We observed a significant multiplicative interaction between the Ile143Val polymorphism and pack-years of smoking on endometrial cancer risk (P, interaction, 0.04); the inverse association of pack-years with endometrial cancer risk was limited to the 143Val carriers (P, trend, 0.01). Compared with women who had the Ile/Ile genotype and never smoked, the 143Val carriers who had >30 pack-years of smoking had a significantly decreased risk of endometrial cancer (OR, 0.41; 95%CI, 0.19-0.86). These data suggest that these two polymorphisms may influence endometrial cancer risk.
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PMID:Polymorphisms in O6-methylguanine DNA methyltransferase and endometrial cancer risk. 1677 93

Leucine-rich repeat-containing G protein-coupled receptor (LGR)-5 is a recently identified marker of stem cells in adult intestinal epithelium and hair follicles. Because of this characteristic, we studied the status of Lgr5 expression in the mouse uterus under various conditions. Lgr5 is highly expressed in the uterine epithelium of immature mice and is dramatically down-regulated after the mice resume estrous cycles. Surprisingly, whereas its expression is up-regulated in uteri of ovariectomized mice, the expression is down-regulated by estrogen and progesterone via their cognate nuclear receptors, estrogen receptor-alpha and progesterone receptor, respectively. Using a mouse endometrial cancer model, we also found that Lgr5 is highly expressed in the epithelium during the initial stages of tumorigenesis but is remarkably down-regulated in fully developed tumors. Lgr5 is a downstream target of Wnt signaling in the intestine. Genetic evidence shows that either excessive or absence of Wnt signaling dampens Lgr5 expression in the uterus. Collectively, our results show that Lgr5 expression in the mouse uterine epithelium is unique and dynamically regulated under various physiological and pathological states of the uterus, suggesting that this orphan receptor has important functions in uterine biology. However, identifying definitive uterine function of LGR5 will require further investigation using conditional deletion of uterine Lgr5 because systemic deletion of this gene is neonatally lethal.
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PMID:In pursuit of leucine-rich repeat-containing G protein-coupled receptor-5 regulation and function in the uterus. 1979


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