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

Aromatase (CYP19) activity in malignant endometrium presents local mechanism with potential ability to support tumor growth. The data on interrelation between activity of this enzyme and its mRNA signal in endometrial cancer (EC) tissue are very scarce and inconclusive. To correct this gap we studied aromatase activity and gene expression totally in 19 samples of EC (17 of them -- from postmenopausal women) collected during surgery. Aromatase activity was evaluated by tritium water release assay and CYP19 gene expression -- with rt-PCR. Additionally, all studied EC cases were divided on the basis of case history and some characteristics of host and tumor and in accordance with existing classification into cases belonging to type I or II of the disease (correspondingly, 13 and 6 observations). Positive correlation between enzyme activity and CYP19 mRNA signal (R(s)=+0.63, p<0.05) was revealed in the whole group of studied samples. Aromatase activity varied in evaluated material between 1.45 fM/mg prot./hr and 11.49 fM/mg prot./hr, and in type II cases it was higher (7.27+/-0.96 fM/mg prot/hr) than in type I observations (4.96+/-0.66 fM/mg prot./hr, p=0.066). CYP19 mRNA expression was not revealed in 6 cases and all of them belonged to the type I of disease. Thus, although type II of EC is frequently considered as hormone non-dependent, increased ability of this tumor type to estrogen biosynthesis (on CYP19 gene and protein level) may lead to reconsideration of such conclusion and warrants further investigation.
 ...
PMID:CYP19 gene expression and aromatase activity in endometrial cancer tissue: importance of the type of the disease. 1580 Jul 9

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)(n) repeat polymorphism in intron IV as well as a 3'UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case-control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989-1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning > 123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency > or = 5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13-2.48) to 2.07 (95% CI 1.33-3.23), comparing variant allele carriers to wild-type homozygotes. We observed significant interactions between menopausal status and 2 of the high-risk loci (p = 0.03 and p < 0.01), with > 2-fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high-frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women.
 ...
PMID:CYP19 (aromatase) haplotypes and endometrial cancer risk. 1580 Sep 24

(1) For postmenopausal women with hormone-receptor-positive breast cancer, the reference adjuvant treatment after surgical excision is tamoxifen (an anti-estrogen), taken orally at a dose of 20 mg/day for 5 years. (2) Anastrozole is the first aromatase inhibitor to be licensed for this use in France. (3) Marketing authorisation was based on the short-term results of a double-blind trial comparing anastrozole (1 mg/day) with tamoxifen (20 mg/day) in 9366 women. The trial is planned to last five years. The results obtained after median follow-up of 4 years showed no difference between the groups in overall survival (109 deaths in each group). But first pathological events were significantly less frequent in the group taking anastrozole (13% versus 15%). Note that these results are undermined by a number of methodological flaws, including relatively short follow-up and definition of relapses using an endpoint mixing heterogeneous prognostic factors. (4) Musculoskeletal disorders, fractures (7.1% versus 4.4%) and hypercholesterolemia were statistically more common with anastrozole than with tamoxifen. Women taking anastrozole found their sex lives less satisfactory than women taking tamoxifen. The following adverse events were statistically less common with anastrozole than with tamoxifen: hot flushes (35.0% versus 40.3%), metrorrhagia, venous thromboembolism (1.1% versus 1.8%), ischaemic stroke (1.1% versus 2.3%), and endometrial cancer (3 versus 15 cases at 4 years). (5) In practice, anastrozole may be beneficial for women who cannot use tamoxifen, such as those at high risk of thrombosis. Anastrozole costs ten times more per day than tamoxifen. Tamoxifen remains the reference adjuvant treatment for all other women.
 ...
PMID:Anastrozole: new indication. Adjuvant treatment of non metastatic breast cancer: useful for some patients. 1587 34

Prospectively, the relationship between androgen levels in the utero-ovarian circulation, aromatase activity in endometrial and body fat tissue, and the presence or absence of endometrioid endometrial cancer was studied in postmenopausal women. In 43 women with endometrioid endometrial cancer and 8 women with a benign gynecological condition, a hysterectomy with bilateral salpingo-oophorectomy was performed. Using tritium water-release assays, aromatase activities in endometrial and body fat tissue were determined and related to the steroid levels from the peripheral and the utero-ovarian venous circulation (estradiol, androstenedione, testosterone) and to the presence or absence of endometrial cancer. Significant aromatase activity was found in both benign and malignant endometrial tissue samples. Aromatase activity in samples of endometrial tissue and in samples of body fat did not correlate with steroid levels in peripheral or utero-ovarian venous blood. Aromatase activity in samples of benign or malignant endometrium did not differ. Remarkably, in four women with mainly poorly differentiated endometrial cancer, very high aromatase activity was found in endometrial tissue. It is likely that multiple pathogenetic pathways exist that eventually lead to the formation of endometrioid endometrial cancer. The local availability of androgens and the finding that aromatase activity is present in both endometrial cancer and benign endometrial tissue support the hypothesis that aromatase activity in the endometrium may play a role in malignant transformation by converting androgens into mitogenic estrogens in the endometrial tissue.
 ...
PMID:Is aromatase cytochrome P450 involved in the pathogenesis of endometrioid endometrial cancer? 1588 81

In a review of current information on aromatase inhibitors (AIs) and their use in breast cancer treatment and prevention, published reports were obtained through a Medline search. Tamoxifen, a selective estrogen receptor modulator, is approved for use in metastatic breast cancer (MBC), the adjuvant treatment of breast cancer, and the prevention of breast cancer in women at high risk. The 50% reduction in breast cancer incidence seen with tamoxifen is significant for women at increased risk but is accompanied by notable toxicities such as thrombotic events and endometrial cancer. Therefore, the development of other effective agents with less toxicity would be a major advance in breast cancer prevention. Aromatase inhibitors, recently approved for the treatment of MBC and in the adjuvant setting, are proving to be slightly more effective than tamoxifen therapy. These drugs, approved for use in only postmenopausal women, inhibit the enzyme aromatase and thereby lower circulating functional estrogen. To date, the most concerning side effect of these agents is an increase in fracture rate. Compared with tamoxifen, thrombotic events and endometrial cancer rates are much lower. Ongoing data from the Arimidex, Tamoxifen, Alone or in Combination trial continue to favor anastrozole over tamoxifen in the reduction of primary contralateral breast cancers. This information has prompted breast cancer chemoprevention trials with AIs. Although tamoxifen is the gold standard for prevention therapy, results of ongoing studies may indicate a role for AIs in the prevention of breast cancer.
 ...
PMID:Aromatase inhibitors for the treatment and prevention of breast cancer. 1589 70

The clinical and endocrine-related effects of 2-week preoperative treatment of endometrial carcinoma patients with a non-steroid inhibitor of letrozole aromatase (femara 2.5 mg/day, n=10) and a steroid inactivator of the enzyme (exemestane 25 mg/day, n=13) were compared. In the first group, pain relief in the lower part of the belly and/or decreased uterine discharge were reported in two cases, as well as a 31% drop in the mean endometrial M-echo (ultrasound) signal. In the exemestane group, two patients revealed moderate uterine discharge decrease matched by a 15.6% decrease in M-signal intensity; no tumor was detected in another patient on completion of the course. Letrozole effect was relatively greater when such parameters as tumor-tissue aromatase level, estrogen concentration in vaginal smear and blood-cholesterol, FSH and LH levels were taken into consideration. However, exemestane therapy involved a relatively sharper drop in the levels of tumor receptors of progesterone and a significantly higher estrogen/progesterone receptor ratio. Hence, no matter how short treatment duration was, both steroid and non-steroid aromatase inhibitors induced effects predominantly associated with lowering estrogen production in endometrial carcinoma patients. This makes a case for further clinical trials of these drugs to deal with the pathology.
 ...
PMID:[Comparison of letrozole and exemestane used in non-adjuvant therapy of endometrial carcinoma]. 1590 11

Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p=0.02). Although no positive correlation was revealed between AA in EC tissue and percentage of cells with DNA damage in normal endometrium from the same patients, the rate of DNA damage (percent of comets, comet's tail average length, etc.) was higher in intact endometrium collected from patients with type II of the disease. In 19 tumor samples, CYP19 gene expression was evaluated by RT-PCR and level of mRNA signal demonstrated positive correlation with AA (R(s)=+0.63, p=0.05) in the whole this material. Of note, though, CYP19 mRNA expression was not revealed in six cases, and all of them belonged to the type I of disease. Finally, in 23 EC patients (15 with type I and 8 with type II of the disease) effects of 2 weeks treatment with letrozole (10 pts) and exemestane (13 pts) were evaluated in neoadjuvant setting. Although diminishing of endometrial M-echo signal and the increases in FSH and LH concentration after treatment were more pronounced in type I patients, decrease in tumor PR content (p=0.04) was more revealing in patients with type II of EC; besides, the decreases in AA in tumor tissue by the end of treatment were noted predominantly in patients with lower body weight (BMI <27.5). Thus, although type II of EC is frequently considered as hormone-independent, increased ability of this type of the tumor to estrogen biosynthesis (at CYP19 gene and protein level) may lead to the reconsideration of such conclusion and warrants further investigation. The search of possible ethnic differences in AA and in the biologic response to aromatase inhibitors in EC can be of importance too.
 ...
PMID:Aromatase and comparative response to its inhibitors in two types of endometrial cancer. 1593 86

Epidemiological, experimental and clinical data strongly support the possibility that breast cancer can be prevented by using anti-estrogenic interventions in healthy women. Four trials involving over 25,000 women have so far been reported using tamoxifen 20 mg/day or placebo in healthy women to chemoprevent breast cancer, and several trials utilizing raloxifene or aromatase inhibitors are underway. Interim analyses of the Royal Marsden tamoxifen trial and the Italian national trial showed no effect on the early incidence of breast cancer. The NSABP-P1 showed a 49% reduction in early incidence of breast cancer. This was associated with a reduction in osteoporotic fractures but increases in the risks of endometrial cancer, cataract and thromboembolism. The IBIS trial showed a 32% reduction with a two-fold increase in endometrial cancer and in thromboembolic events. Mortality rates of breast cancer in women receiving tamoxifen prophylactically should be monitored and further follow-up of these trials is needed to determine whether tamoxifen provides an overall health benefit or increase specific or overall survival of breast cancer. High-risk women should not be advised to take anti-estrogens outside of a clinical trial setting.
 ...
PMID:Should women be advised to take prophylactic endocrine treatment outside of a clinical trial setting? 1598 Jan 59

Because of its proven efficacy profile based on long-term data, tamoxifen has been the standard adjuvant endocrine therapy for hormone-sensitive early breast cancer for the past 30 years. However, there is well-established evidence that long-term use of tamoxifen is associated with serious side effects. As adjuvant endocrine therapy is generally administered for long periods of time, the safety and tolerability of agents used in this setting are of particular importance. Due to their superior efficacy over tamoxifen, newer agents, such as the third-generation aromatase inhibitors (AIs), are already established therapies for the treatment of advanced breast cancer. In addition, recent trials indicate that the AI anastrozole ('Arimidex') has improved efficacy compared with tamoxifen in the adjuvant setting in postmenopausal women. The other third-generation AIs have reported disease-free survival benefits but not in the absence of prior treatment with tamoxifen; letrozole ('Femara') has been compared with placebo following 5 years of tamoxifen therapy and exemestane ('Aromasin') has been compared with tamoxifen following 2-3 years of prior treatment with tamoxifen. Long-term safety data show that anastrozole also has a more favorable overall safety profile compared with tamoxifen, particularly in terms of life-threatening events such as endometrial cancer and thromboembolism. Anastrozole alone, therefore, provides a new option for adjuvant therapy in postmenopausal women with hormone-receptor-positive early breast cancer. The AIs have differing pharmacological profiles, which may translate into dissimilar adverse event profiles in the adjuvant treatment setting, but patient follow-up in most trials is relatively short to make a valid comparison. It cannot, therefore, be assumed that all AIs will be equally well tolerated in the adjuvant setting. Further data on the long-term safety of AIs other than anastrozole are therefore required to allow overall risk:benefit assessments on these agents to be made.
 ...
PMID:Safety considerations of adjuvant therapy in early breast cancer in postmenopausal women. 1608 29

A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts paracrine and intracrine effects. Tissue-specific promoters distributed over a 93-kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues.
 ...
PMID:Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. 1610 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>