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

To study the functional differences between the two progesterone receptor isoforms (hPRA and hPRB) in human endometrial cancer, two new endometrial carcinoma cell lines were created-one expressing hPRA and one expressing hPRB.A well-differentiated, hPR-negative Ishikawa cell line was stably transfected with either hPRA or hPRB cDNA. Transfected cells were selected, and two cell lines expressing approximately equal amounts of receptor were isolated-one expressing hPRA (PRA-14) and one expressing hPRB (PRB-59). Cell growth experiments revealed a growth-inhibitory response to progestins (MPA and R5020) in the PRB-59 cells but not in the PRA-14 cells. Differences in expression of genes targeted by the two isoforms were studied using a cDNA expression array technique. A different set of genes appeared to be progesterone regulated in the PRA-14 cells than in the PRB-59 cells. None of the genes were regulated by both hPRA and hPRB. Insulin-like growth factor binding protein 3 expression was studied in more detail as an example of a gene regulated in PRB-59 cells but not in PRA-14 cells. We established a new model to study functional differences between the two hPR isoforms in human endometrial carcinoma cells. This model revealed distinctive differences in target gene regulation between the two hPR isoforms. Moreover, antiproliferative actions of progesterone on human endometrial cancer cells could be observed only in the PRB-expressing cell line.
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PMID:Distinct functional differences of human progesterone receptors A and B on gene expression and growth regulation in two endometrial carcinoma cell lines. 1251 94

Estrogens act through specific receptors located in the nuclei of epithelial and stromal cells of the endometrium. Estrogens stimulate the synthesis of these receptors and the progesterone inhibits their synthesis. Estrogens induce the proliferation of the mucosa during the proliferative phase. They also stimulate the synthesis of receptors for the progesterone, which is a prerequisite for progesterone activity. Hyperplasias most of the time do not contain cytological atypia and are developed under a hyperestrogenic background. They contain receptors for estrogen and progesterone, and are able to respond to progestogens. Hyperplasias with cytological atypia are precancerous lesions, associated with an hyperestrogenic or atrophic background. In the later case, they may be focal and are better diagnosed by hysteroscopy. They are best managed by simple hysterectomy. Progesterone may be used if the patient desires to conceive. Endometrial cancers are either associated with an hyperestrogenic or atrophic background. In the later case, they are often of serous or clear cell type. Endometrial effects of antiestrogens are known only for tamoxifene. Tamoxifene has an atrophic effect but sometimes may induce an estrogenic stimulation of the endometrial mucosa through the alpha and beta estrogenic receptors. Polyp is the most frequent abnormality diagnosed but endometrial cancer is significantly more frequently diagnosed than in a control population. It is well differentiated and does not modify the survival of the patient.
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PMID:[Effect of estrogens and antiestrogens on the endometrium]. 1266 Dec 81

The role of hormonal factors, in particular unopposed estrogens, on endometrial cancer occurrence is well established. Progesterone deficiency has also been suggested as a possible risk factor. Alcohol use has been shown to be associated with elevated estrogen levels and reduced progesterone. Epidemiologic studies, however, have not offered much support for a positive association between alcohol intake and endometrial cancer, with results generally indicating no association or suggesting an inverse relationship with endometrial cancer. However, certain methodologic limitations, such as small sample size, limited range of alcohol intake, and confounding may have explained those findings. Moreover, there are some unexplored aspects of the possible effect of alcohol, such as the possible interaction with use of exogenous estrogens, and other factors, that need clarification.
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PMID:Alcohol consumption and endometrial cancer: some unresolved issues. 1279 1

Cancer of the uterine endometrium is a frequent gynecologic malignant disease for which few therapeutic options are available for advanced disease. Progesterone is the normal female hormone that limits growth and proliferation of endometrial cancers; however, progesterone receptors are frequently down-regulated, leading to treatment failures. The current studies explored the effectiveness of adenoviral-mediated progesterone receptor gene transduction in combination with progestin therapy in mouse xenograft models. Pretreatment of cells with progesterone receptor-encoding adenovirus and progestin inhibited the development of s.c. tumors in athymic mice. In the i.p. xenograft model, replacement of both isoforms of progesterone receptor, PRA and PRB, in combination with progestin treatment resulted in a significant 2.6-fold increase in overall survival time compared with control animals. These studies indicate that when progesterone receptor levels are maintained, progestin therapy is effective in limiting tumor growth. Future therapeutic regimens targeted at enhancing progesterone receptor expression have the potential to improve outcomes in women with endometrial cancer.
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PMID:A therapeutic model for advanced endometrial cancer: systemic progestin in combination with local adenoviral-mediated progesterone receptor expression. 1565 63

To clarify what constitutes the adequate management of uterine endometrial carcinoma in young women, we reviewed clinicopathologically 31 patients aged 40 years and younger between January 1991 and June 2004. As a primary treatment, 12 cases chose hormonal treatment with medroxyprogesterone acetate (MPA; 600 mg/day) due to no findings of myometrial invasion and diagnosis of a grade 1, well-differentiated adenocarcinoma. In remaining 19 cases, surgery was performed. All the 19 patients who received surgery as a primary treatment are alive, with no evidence of a recurrence of the disease. In the 12 patients who received hormonal treatment, 8 patients eventually received a hysterectomy because of recurrence or no response to MPA. Of these eight patients, myometrial invasion was recognized in three patients. One of the eight patients died of the metastasized disease to the liver and brain after hysterectomy. After hormonal treatment, 4 of the 12 patients were exempted from surgery and showed no evidence of recurrence. Two patients had viable children. Progesterone receptor was negative in one case that died. Careful consideration should be given to hormonal treatment with MPA for the conservative management of endometrial carcinoma in young women. Moreover, MPA is not always a consistent management for every patient.
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PMID:Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. 1601 20

Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Progesterone therapy obtains overall response rates ranging from 11% to 25% in patients with endometrioid-type tumours, and oral medroxyprogesterone acetate 200mg daily appears to be a reasonable therapeutic option for those lesions that are well differentiated and/or have a high progesterone receptor (PgR) content. However, the activity of progestins is often compromised by the down-regulation of PgR within the target tissues, and therefore therapeutic strategies designed to enhance PgR expression are warranted. Little data are currently available about the new aromatase inhibitors and selective estrogen receptor modulators. As for chemotherapy, the combination of doxorubicin [DOX]+cisplatin [CDDP] achieves overall response rates ranging from 34% to 60%, and the addition of paclitaxel (TAX) seems to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. A phase III study is currently comparing TAX+DOX+CDDP versus the less toxic combination of TAX+carboplatin. Chemotherapy is active against both endometrioid-type carcinoma and uterine serous papillary carcinoma. However, this latter endometrial malignancy is less chemosensitive than the histologically similar high-grade serous ovarian carcinoma. Interesting fields of research are represented by investigational agents directed against specific intracellular signal transduction pathways involved in the proliferation, invasiveness and metastatic spread of endometrial cancer. Mammalian target of the rapamycin (mTOR) inhibitors, epidermal growth factor receptor inhibitors (gefitinib, erlotinib, lapatinib, the monoclonal antibody cetuximab), imatinib, the monoclonal antibody trastuzumab, and the Clostridium perfrigens enterotoxin are currently under evaluation as molecularly targeted therapies for endometrial cancer. Further investigations addressed to better understand the signal transduction pathways that are disregulated in endometrial carcinogenesis could identify novel biological targets suitable for tailored therapies.
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PMID:Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies. 1643 30

Progesterone plays an important role in the regulation of normal endometrium function by binding to progesterone receptor (PR). In endometrial cancer, however, PR is always down-regulated. Previous reports showed that methylation in the promoter region of the PR gene may be responsible for PRB isoform repression. However, the CpG islands in the exon region of the PR gene are much richer and longer than in the promoter region. We hypothesize that methylation in the exon region may also take part in the down-regulation of the PR gene. The methylation status of the first exon of the PR gene in endometrial cell cultures was investigated. Aberrant methylation patterns were observed in the first exon of PR gene, and the methylation density is correlated with the differentiation of different types of endometrial cancer cells. DNA methyltransferase (DNMT) and histone deacetylase inhibitor 5-aza-2'-deoxycytidine (ADC), as well as trichostatin A (TSA), which reverses PR gene expression, were also studied. A combination of ADC and TSA resulted in synergistic effects in inducing PR expression, down-regulation of DNMT1 and DNMT3A, and could also have antigrowth effect on endometrial cancer cells by inducing apoptosis.
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PMID:Down-regulation of the progesterone receptor by the methylation of progesterone receptor gene in endometrial cancer cells. 1755 66

The study was undertaken to investigate the effect of long-term treatment with MPA on the growth and invasiveness of endometrial carcinoma Ishikawa cells and the expression of the subtype of estrogen receptor and progesterone receptor. The human endometrial carcinoma Ishikawa cells were continually exposed to 2.5 micromol/L step-wise increase of MPA. MTT assay, flow cytometry and Matrigel invasion assay were used to detect the effect of MPA on the growth, cell cycle distribution and the invasion capability of the cells respectively. RT-PCR was performed to detect the changes of CyclinD1, MMP2 and MMP9 over different time treatment of MPA. Immunocytochemistry was used to examine the expression of estrogen receptor subtype and progesterone receptor subtype. Endometrial carcinoma Ishikawa cells became resistant to the inhibitory effect of MPA over ten months MPA treatment. The cells resistant to the growth inhibitory effect were named progestin-resistant Ishikawa cells and the cells which the progestin-resistant originated from were named the parent Ishikawa cells. The effects of MPA shifted from growth and invasiveness inhibitory effects on the parent Ishikawa cells to stimulatory effect on the progestin-resistant Ishikawa cells. Consistent with the phenomena, the treatment with MPA on Ishikawa cells resulted in statistically significant decreases of CyclinD1, MMP2 and MMP9 gene expression, reversely, the treatment with MPA on the progestin-resistant Ishikawa cell resulted in statistically significant increases of CyclinD1, MMP2, MMP9 gene expression. Immunocytochemical analysis showed reduced ERalpha and PR-B expression and increased ERbeta expression in the progestin-resistant Ishikawa cells compared with parental Ishikawa cells. From the experiment, it was concluded that the prolonged treatment with MPA on Ishikawa cell could give rise of the resistant effect of MPA, the effect of MPA on the growth and invasiveness capability of endometrial carcinoma shifted from inhibitory to stimulatory. The imbalance of ER subtype and PR subtype might contribute to the mechanisms involved in the progesterone resistance over long-term MPA treatment.
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PMID:[Influence of long-term treatment with MPA on the biological character of endometrial carcinoma Ishikawa cell]. 1758 Jun 63

Progesterone and estrogen are critical regulators of uterine receptivity. To facilitate uterine remodeling for embryo attachment, estrogen activity in the uterine epithelia is attenuated by progesterone; however, the molecular mechanism by which this occurs is poorly defined. COUP-TFII (chicken ovalbumin upstream promoter transcription factor II; also known as NR2F2), a member of the nuclear receptor superfamily, is highly expressed in the uterine stroma and its expression is regulated by the progesterone-Indian hedgehog-Patched signaling axis that emanates from the epithelium. To further assess COUP-TFII uterine function, a conditional COUP-TFII knockout mouse was generated. This mutant mouse is infertile due to implantation failure, in which both embryo attachment and uterine decidualization are impaired. Using this animal model, we have identified a novel genetic pathway in which BMP2 lies downstream of COUP-TFII. Epithelial progesterone-induced Indian hedgehog regulates stromal COUP-TFII, which in turn controls BMP2 to allow decidualization to manifest in vivo. Interestingly, enhanced epithelial estrogen activity, which impedes maturation of the receptive uterus, was clearly observed in the absence of stromal-derived COUP-TFII. This finding is consistent with the notion that progesterone exerts its control of implantation through uterine epithelial-stromal cross-talk and reveals that stromal-derived COUP-TFII is an essential mediator of this complex cross-communication pathway. This finding also provides a new signaling paradigm for steroid hormone regulation in female reproductive biology, with attendant implications for furthering our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in such human reproductive disorders as endometriosis and endometrial cancer.
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PMID:COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. 1759 85

The effects of estrogen and progesterone on the expression of estrogen-metabolizing enzymes such as catechol-O-methyl transferase (COMT) are not known. COMT converts genotoxic catecholestrogens to anticarcinogenic methoxyestrogens in the endometrium. The aim of this study is to investigate the effect of progesterone on COMT expression in well-differentiated endometrial cancer cells. The wild-type Ishikawa cell line as well as progesterone receptor A- or progesterone receptor B-transfected Ishikawa cells were used for in vitro studies. The regulation of COMT expression by progesterone was studied using Western blots, Hoechst dye DNA proliferation studies, and wild-type and/or site-directed mutagenesis of COMT promoter 1-luciferase reporter gene. Progesterone upregulated COMT protein expression in Ishikawa cells through progesterone receptor A isoform. COMT promoter activity was differentially regulated by the 3 half-site progesterone response elements in the COMT promoter. High doses of 2-ME2 inhibited Ishikawa cell proliferation. These data suggest that COMT expression is hormonally regulated in well-differentiated human endometrial cancer cells. COMT regulation and 2-ME2 production in the endometrium may affect endometrial carcinogenesis.
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PMID:Progesterone-mediated regulation of catechol-O-methyl transferase expression in endometrial cancer cells. 1808 88


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