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 development and growth of gynecological cancers are related to steroid hormone actions. Alternatively, this prompts us to study biological contribution of sex steroids for invasion and metastasis in gynecological cancers. The first step of metastasis is the detachment of tumor cells. The adherens junction forms a main cell-to-cell junctional complex, mainly consisting of E-cadherin, alpha- and beta-catenins, etc. Estrogen suppressed the expression of their mRNAs, and the adhesive function of cells via adherens junction in endometrial cancer cells. Progestin and danazol reversed the estrogen-induced suppression. Estrogen enhanced invasiveness of endometrial cancer cells though the reconstituted basement membrane and interstitium using the Boyden chamber. Progestin reduced the estrogen-induced invasiveness. The final step of metastasis is tumor-derived neovascularization for growth of metastatic cancer cells. Progestin inhibited basic fibroblast growth factor (FGF) activity, which mainly contribute to tumor-derived neovascularization, regardless of growth-inhibition in some endometrial cancers. Progestin inhibits basic FGF in well-differentiated (WD) endometrial cancer cells, but not in poorly differentiated (PD) endometrial cancer cells. TNP470, a inhibitor of vessel endothelial proliferation, inhibited directly basic FGF in the PD. Therefore, the adequate combination therapy of progestin and TNP470 could efficiently inhibit angiogenic potential of heterologous endometrial cancers. The ratio of estrogen receptor exon 5 splicing variant (ER delta E5) to wild type-ER mRNA expression increased in some metastatic lesions of cancers. The dominant expression of ER delta E5 mRNA might be related to metastatic potential of gynecological cancers. Progesterone receptor from A (PR-A), initiated from in-frame AUG present in the PR from B (PR-B) mRNA, lacks the N-terminal 164 amino acids of PR-B, and acts as a progestin-dependent, trans-dominant repressor of PR-B function and other steroid receptor function. The expression of PR-B mRNA was dominantly expressed in all metastatic gynecological cancers given. This might be related to metastatic potential of gynecological cancers. To know tumorigenic potential of sex steroid receptors, ER, PR-A and PR-B genes were transfected to NIH3T3 cells. Transfected cells with PR-A gene alone formed a few colonies in double soft agar. On the other hand, the cells with PR-B and ER genes under the presence of estradiol formed plenty of colonies. Therefore, overexpression of PR-B under the absence of PR-A might be related to tumorigenic potential. In conclusion, estrogen could enhance some steps of metastasis in endometrial cancers, and progestin could inhibit the estrogen-induced events, regardless of growth-inhibition. Relative over-expression of ER exon 5 splicing variant, and PR-B might contribute to metastatic potential in gynecological cancers.
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PMID:[Endocrinological contribution for invasion and metastasis in gynecological cancers]. 880 31

Many of the most common cancers occur in sites that are under hormonal regulation by the steroid sex hormones. These include the breast, ovary, endometrium and possibly the colon for women, and the prostate and testes for men. Much information on chemoprevention of these cancers has accrued indirectly as a result of the use of estrogens and progestagens for contraception or postmenopausal hormone replacement therapy. Estrogen-based contraceptives clearly reduce the risk of ovarian cancer, but without an opposing progestagen they increase the risk of endometrial cancer. Progestagens reduce the risk of endometrial cancer and when used premenopausally appear to be able to more than counteract the carcinogenic effect of exogenous estrogens at this site. The effect of oral contraceptives on breast cancer appears to be quite minimal, but probably increases risk when taken for long periods at a young age. Recent studies suggest that the use of an agonist of leuteinizing hormone releasing hormone as a contraceptive may reduce the risk of breast cancer. Estrogens used in postmenopausal hormone replacement therapy increase the risk of both breast and endometrial cancer, but addition of a progestagen may counteract the increased risk to the endometrium. The agent most intensively under study for breast cancer prevention is tamoxifen, which has proven effectiveness as a therapeutic agent. When taken for more than two years it has been shown to reduce the occurrence of new contralateral tumours by about 50% in women who have had breast cancer. Three large international trials are currently evaluating its role in a preventive setting. For men, interest has centred on the use of 5 alpha-reductase inhibitors to block the prostatic conversion of testosterone to dehydrotestosterone and potentially inhibit the development of prostate cancer. The 5 alpha-reductase inhibitor finasteride is currently under test in a prevention trial.
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PMID:Medicinal drugs with hormonal activity as chemopreventive agents. 892 22

Transcription-modulating drugs achieve their therapeutic effects through the modulation of gene transcription. To understand how selectivity is achieved, four groups of such drugs - including immunosuppressants, estrogen analogs, the antidiabetic thiazolidinediones, and the anti-inflammatory salicylates - will be discussed. The immunosuppressants cyclosporin A and FK506, when complexed with immunophilins, inactivate the protein phosphatase calcineurin, resulting in the inhibition of interleukin-2 gene activation. Another immunosuppressant, rapamycin, binds to the same immunophilin as FK506 but inactivates a protein kinase p70(s6k). Estrogen analogs tamoxifen and rolaxifene antagonize one estrogen receptor transactivation function (AF-2) and agonize another (AF-1). They modulate expression of a wide variety of genes, including transforming growth factor-alpha, insulin-like growth factor-1, and transforming growth factor-beta3, which are important for breast and endometrial cancer proliferation and bone maintenance respectively. The antidiabetic drugs thiazolidinediones bind and activate peroxisome proliferator-activated receptor gamma and suppress insulin resistance mediated by tumor necrosis factor-alpha. Salicylates inhibit transcription factor NFkappaB, which is important for immune and inflammatory responses. Continuing understanding of molecular mechanisms of such drugs not only helps to identify better drugs for these targets but should also provide an insight into developing future transcription-modulating drugs with better selectivity and reduced toxicity.
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PMID:Transcription-modulating drugs: mechanism and selectivity. 893 43

1. The levels of basic fibroblast growth factor (FGF) expression and secretion and its messenger ribonucleic acid (mRNA) expression in well-differentiated endometrial cancer (Ishikawa) cells were significantly increased by estradiol. 2. This increase was significantly inhibited by tamoxifen, progestins (progesterone, medroxyprogesterone acetate [MPA], and 17 alpha-hydroxyprogesterone), and to some extent danazol, but not by terahydrocortisol and hydrocortisone. 3. Estrogen might stimulate the basic FGF secretion of endometrial cancer cells, at least for neovascularization, and antiestrogenic compounds may inhibit the estrogen-induced event.
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PMID:Antiestrogenic compounds inhibit estrogen-induced expressions of basic fibroblast growth factor and its mRNA in well-differentiated endometrial cancer cells. 959 98

In recent years, reports of favourable effects of estrogen therapy on cardiovascular morbidity and mortality have led to enthusiasm for widespread use of estrogens by postmenopausal women. Guidelines for estrogen therapy issued by the American College of Physicians include the statement "Women who have coronary heart disease are likely to benefit from hormone therapy". What evidence support this recommendation? More than 30 observation studies have examined the effect of estrogen replacement therapy on cardiovascular event and all cause mortality. In addition there have been 13 case controlled studies. The majority showed lower morbidity and mortality from coronary heart disease among users of postmenopausal estrogens than among non-users. Recently, 2 meta-analyses estimated the reduction in coronary heart disease associated with estrogen use to be in the range of 35 to 44%, respectively. All of these observational studies share a fatal flaw: Women who take estrogens are different from women who do not. Some differences have been measured, others have not. Women who take estrogens are on average better educated, healthier, have higher incomes and have better access to health care. These difference rather than the estrogens may account for much of the lower risk of heart disease. At this time we cannot tell from these observational studies what the real benefit of estrogens on coronary heart disease might be. Estrogen replacement therapy is not without risk. Estrogens increase the risk of endometrial carcinoma approximately 6-fold, an effect that is eliminated by the addition of progestins. Controversy continues over whether estrogen replacement increases the risk of breast cancer. A number of prospective randomized studies are now under way that will establish whether estrogen replacement therapy definitely reduces the risk of cardiovascular disease in women with and without coronary lesions and whether it increases the risk of breast cancer. Until the results of these trials are available claims on the definite usefulness of hormone supplementation to prevent coronary heart disease in postmenopausal women remain premature. In the light of the probable usefulness estrogen replacement therapy for the prevention of cardiovascular events should be recommended for women with increased risk for or definitively proven coronary heart disease.
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PMID:[Estrogens for prevention of coronary heart disease?]. 930 98

Estrogen biosynthesis in adipose tissue increases with age and obesity, and has been implicated in the development of endometrial cancer and breast cancer. In normal human adipose tissue, expression of the CYP19 gene which encodes aromatase P450, the enzyme responsible for estrogen biosynthesis, is regulated by a distal promoter, namely promoter I.4. Stimulation of expression in adipose stromal cells by members of the type 1 cytokine family, i.e. interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), is mediated via a Jak-STAT3 signaling pathway and a GAS element upstream of promoter I.4. In contrast, aromatase expression in breast adipose tissue proximal to tumor is increased three- to four-fold to the utilization of another promoter, namely promoter II, proximal to the translation initiation site. In the present report, we show that prostaglandin (PG) E2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE2 acts via EP1 and EP2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in the maximal expression of promoter II-specific CYP19 transcripts. Because PGE2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.
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PMID:Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture. 936 91

Estrogen exerts a variety of biological effects on human reproductive tissues. However, little is understood about the estrogenic effect on human endometrial cells in vitro. This study was designed to investigate estrogen action on c-myc and c-fos oncogenes and lactoferrin gene expression in human endometrial carcinoma RL95-2 cells. The results indicate that estrogen can induce c-myc oncogene expression in 4 h. Neither c-fos nor the lactoferrin messenger was detectable, nor could they be induced by estrogen. Transfection with human estrogen receptor expression vector to the RL95-2 cells does not restore the estrogen responsiveness. In addition to estrogen, epidermal growth factor (EGF) and tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) can also induce c-myc expression with no effect on c-fos or lactoferrin expression. Our data suggest that the c-myc oncogene in human endometrial carcinoma RL95-2 cells is the sensitive target gene for steroid hormone and growth factor action.
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PMID:Identification of the estrogen sensitive marker in human endometrial carcinoma RL95-2 cells. 939 49

Estrogen receptor-related orphan receptor alpha 1 is a member of the steroid/thyroid nuclear receptor superfamily. We have previously cloned the human estrogen receptor-related orphan receptor alpha 1 (hERR alpha 1) cDNA and demonstrated that it enhances estrogen responsiveness of the lactoferrin gene promoter in transfected human endometrial carcinoma cells. In the present study, we used the hERR alpha 1 cDNA as a probe and isolated the mouse homologue of ERR alpha 1 from the cDNA libraries of the brain and kidney. Sequence comparison between human and mouse ERR alpha 1 (mERR alpha 1) revealed that the homologies are 89% in nucleotides and 97% in amino acids. By electrophoresis mobility shift assay, we showed that the glutathione S-transferase-mERR alpha 1 fusion protein produced in a bacterial system bound to the human ERR alpha 1 DNA-binding element. Mouse uterine nuclear extract also interacted with this DNA element and produced three complexes in the mobility shift assay, one of which was supershifted by the hERR alpha 1 antiserum. A 2.2 kbp transcript was detected by Northern analysis in all adult mouse tissues tested; however, large variations in the amount of ERR alpha 1 mRNA were found among them. Multiple immunoreactive forms of mouse ERR alpha 1 were detected by Western analysis in non-reproductive tissues, whereas a major 53 kDa protein was found in reproductive tissues such as uterus, cervix and vagina. Diethylstilbestrol (DES) stimulated the expression of ERR alpha 1 mRNA in the uterus of 19-day-old mouse. We showed that DES and estradiol, but not progesterone or dexamethasone, enhanced the level of immunoreactive ERR alpha 1 in the mouse uterus. These results demonstrated that the ERR alpha 1 is an estrogen-responsive gene in the mouse uterus and provides a model system with which to study the biological roles of this nuclear orphan receptor.
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PMID:The mouse estrogen receptor-related orphan receptor alpha 1: molecular cloning and estrogen responsiveness. 946 Jun 51

Estrogen replacement therapy (ERT) after menopause prevents the development of osteoporosis and reduces the risk of fracture. Other potential benefits are cardioprotection--probably related to the effects of estrogen on lipid profile and fibrinogen levels--and a delay in the onset of Alzheimer's disease and perhaps amelioration of the disease. ERT, however, increases the risk of endometriosis and endometrial cancer unless given with a progestin for at least 10 days per menstrual cycle. It also results in a small but real increase in breast cancer. Alendronate, a bisphosphonate, is the first serious competitor of conjugated equine estrogen for the treatment of osteoporosis. Nearing FDA approval are so-called designer estrogens (e.g., raloxifene), which may selectively prevent osteoporosis with little or no effects on endometrial and breast tissue.
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PMID:Prevention and treatment of osteoporosis: does the future belong to hormone replacement therapy? 950 3

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


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