UMLS:C0476089 - FACTA Search

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

The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER)alpha, and ERbeta mRNA were investigated in rat brain. Estradiol-17beta (E(2)) treatment following OVX reduced the levels of ERalpha mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreacive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ERalpha. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid beta were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E(2). ERalpha cDNA transfected PC 12 cells elaborated more neurite-like processes with E(2). In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD.
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PMID:Alzheimer's disease and estrogen. 1138 81

Estradiol production is most commonly thought of as an endocrine product of the ovary; however, there are many tissues that have the capacity to synthesize estrogens from androgen and to use estrogen in a paracrine or intracrine fashion. In addition, other organs such as the adipose tissue can contribute significantly to the circulating pool of estrogens. There is increasing evidence that in both men and women extraglandular production of C(18) steroids from C(19) precursors is important in normal physiology as well as in pathophysiologic states. The enzyme aromatase is found in a number of human tissues and cells, including ovarian granulosa cells, the placental syncytiotrophoblast, adipose and skin fibroblasts, bone, and the brain, and it locally catalyzes the conversion of C(19) steroids to estrogens. Aromatase expression in adipose tissue and possibly the skin primarily accounts for the extraglandular (peripheral) formation of estrogen and increases as a function of body weight and advancing age. Sufficient circulating levels of the biologically active estrogen estradiol can be produced as a result of extraglandular aromatization of androstenedione to estrone that is subsequently reduced to estradiol in peripheral tissues to cause uterine bleeding and endometrial hyperplasia and cancer in obese anovulatory or postmenopausal women. Extraglandular aromatase expression in adipose tissue and skin (via increasing circulating levels of estradiol) and bone (via increasing local estrogen concentrations) is of paramount importance in slowing the rate of postmenopausal bone loss. Moreover, excessive or inappropriate aromatase expression was demonstrated in adipose fibroblasts surrounding a breast carcinoma, endometriosis-derived stromal cells, and stromal cells in endometrial cancer, giving rise to increased local estrogen concentrations in these tissues. Whether systemically delivered or locally produced, elevated estrogen levels will promote the growth of these steroid-responsive tissues. Finally, local estrogen biosynthesis by aromatase activity in the brain may be important in the regulation of various cognitive and hypothalamic functions. The regulation of aromatase expression in human cells via alternatively used promoters, which can be activated or inhibited by various hormones, increases the complexity of estrogen biosynthesis in the human body. Aromatase expression is under the control of the classically located proximal promoter II in the ovary and a far distal promoter I.1 (40 kilobases upstream of the translation initiation site) in the placenta. In skin, the promoter is I.4. In adipose tissue, 2 other promoters (I.4 and I.3) located between I.1 and II are used in addition to the ovarian-type promoter II. In addition, promoter use in adipose fibroblasts switches between promoters II/I.3 and I.4 upon treatments of these cells with PGE(2) versus glucocorticoids plus cytokines. Moreover, the presence of a carcinoma in breast adipose tissue also causes a switch of promoter use from I.4 to II/I.3. Thus there can be complex mechanisms that regulate the extraglandular production of estrogen in a tissue-specific and state-specific fashion.
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PMID:Estrogen production and action. 1151 61

A role for activins in regulating cellular transformation is suggested by the alpha-inhibin knockout mouse in which development of gonadal tumors is associated with elevated activin levels. It was the purpose of the current study to determine whether activin had similar actions on endometrial cell lines, specifically on a well differentiated estrogen-responsive endometrial adenocarcinoma cell line (ISH) and estrogen-unresponsive cells (HEC-50) obtained from a poorly differentiated endometrial adenocarcinoma. Activin was secreted by both adenocarcinoma cell lines. Using reverse transcription-PCR, messenger RNA type I and type II activin receptor subtypes were detected in both cell lines: expression of IB and IIB was approximately three- to fourfold greater in ISH cells than in HEC-50 cells, while activin receptor IA and IIA messenger RNA levels were approximately equal in both cell lines. Activin treatment (30-300 ng/ml) caused a dose- and time-dependent inhibition of ISH cells proliferation and resulted in a significant decrease in Bcl-2 protein and mRNA levels. No difference was observed in Bax expression. There was no significant effect of activin when the cultures of ISH cells were exposed to 17beta-estradiol. In contrast, activin showed a weak, but significant, mitogenic effect on HEC-50 cells without modifications in Bax and Bcl-2 mRNA and protein levels. The results demonstrate that activin is a regulator of endometrial cancer cell growth. 17beta-Estradiol may promote resistance of estrogen-responsive endometrial cancer cells to the growth-retarding effects of activin and one of the mechanisms might be a down-regulation of the activin receptors.
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PMID:Regulation of endometrial adenocarcinoma cell proliferation by Activin-A and its modulation by 17beta-estradiol. 1208 79

The steroid hormones are recognized and fixed by special cytoplasmic proteins in the target tissue called receptors. Most circulating natural steroids are tied to transport proteins. Estradiol and progesterone are active as such in the receptor cells, but testosterone is transformed into dihydrotestosterone in situ under the influence of the enzyme 5 alpha reductase before combining with the receptor. Receptivity may be exacerbated or reduced. Exacerbation is particularly likely when physiological control mechanisms are deficient. Testosterone has a biological effect at the level of the Wolfian apparatus in the embryo and in the muscle and bone of the adult. The activity of perineal 5 alpha reductase implicated in these phenomena and the hepatic 5 alpha reductase activity implicated in the degradation of testosterone are found in both sexes and are under genetic influence independent of the male hormone. Problems in receptivity to the male hormone are well known to clinicians. Hirsutism, whatever its cause, is always associated with great cutaneous 5 alpha reductase activity. The use of antiandrogens derived from synthetic progestagens has transformed treatment of hirsutism. Male pseudohermaphrodism may be secondary to an insufficient testosterone production or to primary resistence to the male hormone, in which case the plasma concentration of testosterone is always greater than normal. The characteristic case is of a deficit of 5 alpha reductase and feminization of the testicle. 5 alpha reductase deficiency causes sexual ambiguity at birth. Absence of the testosterone receptor at both the perineal and public levels explains why attempts to treat these disorders with high doses of testosterone or dihydrotestosterone always fail. Problems in receptivity to the male hormone have been found to cause other pathologies, such as severe oligospermia. The quantity of estradiol and progesterone receptors varies according to the volume of circulating estradiol and of progesterone. Progesterone is a natural antiestrogen; it limits the activity of estradiol by favoring the transformation of estradiol into estrone and decreases the synthesis of estradiol receptors. The normal endometrium may become hyperplasic after menopause, the 1st stage in development of endometrial cancer. Continuous estrogen stimulation not countebalanced by progesterone permits the transformation. Study of estradiol and progesterone receptors in mammary fibroadenomas has shown that estradiol receptors increase to a maximum in the preovulatory period and diminish in the luteal phase. The increase in estradiol is followed by an increase in progesterone receptors. Since 1971 it has been apparent that breast cancer susceptible to improvement by hormonal treatment were rich in estrogen receptors.
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PMID:[Receptivity to the sex steroids, physiopathological aspects]. 1231 77

Levels of aromatase, a key enzyme in estrogen biosynthesis, were assayed in tumor tissue sampled from 25 patients with endometrial cancer. In addition, estradiol concentrations were compared in normal and altered endometrial tissue from 78 patients suffering uterine cancer. Unlike breast cancer, aromatase was not detectable in altered endometrium unless tissue estrogens could be identified in both normal and tumor tissue. Hence, aromatase presence served as an indicator of malignant transformation. Its concentration in samples of uterine tissue varied 0-28.4 fM/mg protein/hr (an average of 12.9(1.7 fM/mg protein/hr). There was hardly any correlation between this level, on the one hand, and menopause and body mass, on the other. Yet, it tended to increase in step with stage of disease and cell differentiation decline. Estradiol concentrations in malignant endometrium in both reproductive and menopausal patients were higher than in macroscopically normal ones, while still cycling women tended to show higher values than menopausal ones. Although there was no significant difference in estradiol levels in the altered endomentrium of patients with pathogenetical patterns of uterine cancer stage I and II, they did show a direct correlation with clinical stage of tumor process and depth of invasion into the underlying myometrium. Hence, unlike estrogens circulating in blood, those contained in tissue ("intratumor") ones did enhance the aggressiveness of endometrial cancer course. It will be for further investigations to show whether it is due to an estrogen fraction being carried away by tumor from the circulation, or estrogens being synthesized by aromatase in tumor itself.
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PMID:[Tumor tissue aromatase and estrogen levels versus clinical course of endometrial cancer]. 1271 71

Numerous studies have suggested that the lifetime dose of unopposed estrogen is a significant risk factor for breast and uterine cancer. Estradiol (E2) plays a putative role as a tumor promoter through interaction with estrogen receptors but can also be metabolized to redox active and/or mutagenic semiquinones and quinones. Similarly, equine estrogens (components of certain hormone replacement therapy preparations) are converted to quinone metabolites. The use of hormone replacement therapy has also been associated with increased breast and endometrial cancer risk. Recently, metabolites of certain equine estrogens have been shown to inhibit human glutathione S-transferases (hGSTs). Since E2 and equine estrogens share similarities in other biological interactions, we have investigated the inhibitory capacity of endogenously formed E2 metabolites toward various hGSTs. The quinone metabolite of 2-hydroxy-17-beta-estradiol (2-OH-E2) was synthesized, and inhibition of hGST-mediated biotransformation of model substrates was assessed. Inhibition of purified recombinant hGSTM1-1 and hGSTA1-1 occurred in a concentration-dependent manner with IC50-values of approximately 250 and 350 nM, respectively. hGSTs M2-2, P1-1 and T1-1 were significantly less sensitive to inhibition. Specific glutathione-conjugates of the estrogen quinone also potently inhibited hGSTM1-1 and hGSTA1-1. Mass spectrometry data indicate that the inhibition was not mediated via covalent adduction. Although we have demonstrated hGST inhibition via E2 metabolites, our findings indicate that the isoform specificity and potency of GST inhibition by endogenous E2 metabolites is different than that of equine estrogen metabolites.
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PMID:Estradiol metabolites as isoform-specific inhibitors of human glutathione S-transferases. 1560 59

Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 micromol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10(-7) mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H2Delta16 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ER(alpha) mRNA and protein without an effect on ER(beta) levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE(2)e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ER(alpha) levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.
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PMID:Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells. 1609 40

Tissue Factor (TF), the initiator of the extrinsic coagulation cascade, is overexpressed in a variety of cancers. TF is also expressed in normal human endometrium but little is known about its expression or regulation in endometrial cancer. We demonstrate herein that TF is expressed in the endometrial adenocarcinoma cell line Ishikawa. Furthermore, epidermal growth factor (EGF) induces a rapid and sustained increase in TF expression. Estradiol and progesterone had no effect on basal or EGF-induced TF expression in Ishikawa cells. In contrast to the pronounced and sustained upregulation at the protein level, EGF treatment elicited only a modest and transient increase in TF mRNA levels. This activity corresponded to the response observed from an exogenous TF promoter construct. However, the induction of TF was abrogated by cycloheximide as well as actinomycin-D, inhibitors or protein- and mRNA-synthesis, respectively, demonstrating that EGF mediates its effect through activation of the TF gene. Fractionation experiments showed that EGF increases TF presence in caveolin-I containing membrane fractions. Coagulation and invasion assays were used to explore the physiological implications of TF regulation. The results demonstrate that EGF-mediated induction of TF increases the procoagulant activity and invasive potential of Ishikawa cells. Furthermore, immunocytochemistry confirmed that TF is regulated by EGF in primary cultures of normal endometrial epithelial cells and malignant tumor cells. In conclusion, EGF-mediated upregulation of TF results in accumulation of this glycoprotein in caveolae-like membrane fractions and increased coagulative and invasive potential. Our results suggest that TF may play an integral role in endometrial carcinogenesis.
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PMID:Tissue factor is regulated by epidermal growth factor in normal and malignant human endometrial epithelial cells. 1611 38

17beta-Estradiol (E2) and its catechol and methoxy metabolites are believed to play important roles in the mechanism of E2-mediated tumor formation. Because conjugation with glucuronic acid lowers tissue levels by facilitating excretion, we have determined the kinetic parameters of the glucuronidation of E2, estrone (E1), and seven phase I metabolites using human liver microsomes. The catechol estrogens 2- and 4-hydroxy-E2/E1 exhibited the highest clearance, exceeding that of E2, E1, and the methoxy metabolites by factors of 6-44. Homotropic activation kinetics were observed for the 3-glucuronidation of E2 but not for any of the metabolites. None of the metabolites affected the kinetics of the 3-glucuronidation of E2. In contrast, the isoflavone daidzein stimulated the formation of E2-3-glucuronide, as has been reported previously. This heterotropic activation by daidzein appears to be specific for the glucuronidation of E2 because daidzein did not affect the glucuronidation of the 2- and 4-hydroxy metabolites of E2. However, daidzein may lower the glucuronidation of 2-methoxy-E2 in vivo due to its preferential glucuronidation. The decreased tissue levels of E2 and increased concentrations of 2-methoxy-E2, as implied by this study and the previous one, may contribute to the protective effect of daidzein against breast and endometrial cancer.
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PMID:Stimulation of estradiol glucuronidation: a protective mechanism against estradiol-mediated carcinogenesis? 1659 14

Estradiol-17beta (E(2)) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor alpha (ERalpha). In this work we show that this signaling is mediated by the insulin-like growth factor 1 receptor (IGF1R) expressed in the epithelium, whose activation leads to the stimulation of the phosphoinositide 3-kinase/protein kinase B pathway leading to cyclin D1 nuclear accumulation and engagement with the canonical cell cycle machinery. This cyclin D1 nuclear accumulation results from the inhibition of glycogen synthase kinase 3beta (GSK3beta) activity caused by an inhibitory phosphorylation by protein kinase B. Once the IGF1 pathway is activated, inhibition of ER signaling demonstrates that it is independent of ER. Inhibition of GSK3beta in the absence of E(2) is sufficient to induce uterine epithelial cell proliferation, and GSK3beta is epistatic to IGF1 signaling, indicating a linear pathway from E(2) to cyclin D1. Exposure to E(2) is the major risk factor for endometrial cancer, suggesting that downstream activation of this IGF1-mediated pathway by mutation could be causal in the progression to ER-independent tumors.
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PMID:Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. 1789 82

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