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

The uterine endometrium responds to unopposed estrogen stimulation with rapid cell proliferation. Progesterone protects the endometrium against the hyperplastic effects of estradiol (E2) through progesterone receptors (PRs), of which two isoforms are expressed: human (h) PRA and PRB. hPRB has a longer NH2 terminus and may function differently from hPRA. Thus, the relative expression of hPRA:hPRB is likely to be important for the action of progesterone. We hypothesized that the hPRA:hPRB ratios may be abnormal in endometrial cancer, leading to a lack of normal progesterone protection against the growth-promoting effects of E2. To test this hypothesis, well-differentiated Ishikawa endometrial cancer cells were compared to poorly differentiated Hec50 and KLE cells. Reverse transcription-PCR was chosen as a sensitive method to detect transcripts for the two forms of PR. The relative expression of PR isoforms under hormonal stimulation was determined by Western blotting. Transient transfections of hPRA and hPRB into endometrial cells allowed the evaluation of the transcriptional activity of each isoform independently on reporter gene transcription under the control of a simple progesterone response element-containing promoter. The effect of coexpressing the estrogen receptor on PR expression was also studied. Ishikawa cells (well-differentiated) express both hPRA and hPRB. Both isoforms, but predominantly hPRB, are up-regulated by E2 and not by tamoxifen or the pure antiestrogen ICI 182,780. Hec50 and KLE cells (poorly differentiated) express only hPRA. No hPRB is present in the poorly differentiated cells, and it is not induced by estrogen receptor expression and/or estrogen treatment. In all cells, hPRB expression, whether endogenous or produced as a result of transfection, acts as a stronger transcription factor than hPRA on a simple progesterone-dependent promoter. We speculate that down-regulation of hPRB may predict for poorly differentiated endometrial cancers that do not respond to progestin therapy.
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PMID:Selective down-regulation of progesterone receptor isoform B in poorly differentiated human endometrial cancer cells: implications for unopposed estrogen action. 958 25

The expressions of two isoforms of human progesterone receptor (PR) are under the control of the two different promoters. Recent studies revealed differences between these isoforms, PRA and PRB, in their expression and function in endometrial cells. Aberrant methylation of normally unmethylated CpG islands has been associated with inactivation of several genes in human cancers. In this study, we investigated the methylation status and the expression of the two different PR isoforms, PRA and PRB, in uterine endometrial carcinoma (UEC) using methylation-specific PCR (MSP), reverse transcription-PCR (RT-PCR), the 5' rapid amplification of cDNA ends method (5'RACE), and immunohistochemical staining. The results of RT-PCR and 5'RACE suggest that only PRB is inactivated, although PRA is activated in all UEC cell lines. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine, restored PRB expression in all cell lines, suggesting that inactivation of this gene is through methylation. By MSP and direct DNA sequencing, PRB was methylated, whereas PRA was unmethylated in all of the cell lines. To determine the methylation status of PRB in UEC patients, we investigated 83 cancerous and 33 normal samples. Sixty-two of 83 cancer samples had only methylated alleles of PRB, although all cancer samples had only unmethylated PRA alleles. Seventy-one of 83 cancer samples were negative for PRB expression. All 62 cancer samples that had only methylated PRB alleles were negative for PRB expression. No significant changes were observed in PRA methylation status or immunohistochemistry positivity in normal and cancer samples. To determine whether de novo methylation of PRB occurred in UEC patients, we studied 32 pairs of cancer and normal samples from the same patient. Twenty of 32 cancer samples had only methylated PRB alleles, although all 32 normal samples had only unmethylated PRB alleles. The loss of unmethylated alleles was well correlated with negativity in immunohistochemical staining for PRB. This is the first report of the selective methylation and the subsequent silencing of PRB in uterine endometrial cancer.
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PMID:Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer. 1119 5

The nuclear receptor for the female hormone progesterone (PR) is widely expressed in uterine cancer. PR is expressed as two proteins (PRA and PRB) with different functions, and in vitro evidence reveals PRA to inhibit PRB function, so the cellular ratio of PRA:PRB is likely to be an important determinant of progesterone action. The relative expression of PRA and B and their involvement in the pathogenesis of endometrial cancer is not known. The aims of this study were to determine PRA and B expression by dual immunofluorescent histochemistry in endometrial adenocarcinomas compared with expression in normal and hyperplastic glands, and to correlate expression in tumors with clinical features including grade. Significantly lower PR levels were found in tumors compared with normal glands and areas of complex atypical hyperplasia within the same specimen. The normal glands expressed both of the isoforms at similar levels, whereas there was increased predominance of one isoform in hyperplastic areas and in tumors, which suggested that the loss of coordinated expression of PR isoforms was an early event in tumor progression. The majority of tumors [27 (58%) of 46] expressed only one PR isoform, and the proportion expressing either PRA or B was the same [14 (30%) of 46, and 13 (28%) of 46, respectively]. One-half of all tumors ([23 (50%) of 46] expressed either PRA only or a predominance of PRA, and a few tumors [10 (22%) of 46] expressed comparable levels of PRA and B. Similar levels of PRA and B were noted only in FIGO grade 1 tumors, whereas higher grades (2 and 3) were associated with a predominance of one isoform. In summary, expression of only one PR isoform was common in endometrial cancers, which indicates that the decreased PR levels observed in these cancers arise from the loss of one PR isoform. Expression of a single PR isoform was associated with higher clinical grade, which suggests a relationship between the loss of PR isoform expression and features of poorer prognosis. Disruption of relative PR isoform expression was observed in complex atypical hyperplasia, which suggests that early alterations in the ratio of PRA:PRB may precede and/or be implicated in the development of endometrial adenocarcinoma. Alterations in the ratio of PR isoform expression are likely to cause disordered regulation of target genes, resulting in altered progestin action in the uterus, and this may be involved in the pathogenesis of endometrial cancer.
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PMID:Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium. 1138 93

Progesterone is a critical steroid hormone that controls cell proliferation and differentiation in the female reproductive tract. Progesterone acts through two nuclear receptor isoforms, progesterone receptors A and B (PRA and PRB, respectively), each with unique cellular effects. Loss of PRB has recently been linked to the development of poorly differentiated endometrial tumors, a lethal form of cancer. To study the molecular effects of progesterone, progesterone receptors were introduced into Hec50co endometrial cancer cells by adenoviral vectors encoding either PRA or PRB. Progesterone induced the cyclin-dependent kinase inhibitors p21 and p27, thereby significantly reducing the percentage of proliferating cells. Cancer cell invasion was also markedly inhibited as measured by Matrigel invasion studies. Similarly, a differentiated, secretory phenotype was induced by progesterone in cells expressing PRB. However, replicative senescence was induced by progesterone only in cells expressing PRA. Expression array analysis followed by confirmatory semiquantitative reverse transcription-PCR experiments demonstrated a significant progesterone-dependent inhibition of expression of a cadre of cellular adhesion molecules, including fibronectin, integrin alpha3, integrin beta1, integrin beta3, and cadherin 6. The level of down-regulation of adhesion molecule expression was significantly greater in the presence of the B isoform, demonstrating that progesterone acts principally through B receptors to inhibit cancer cell invasiveness modulated by adhesion molecules.
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PMID:Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. 1183 May 47

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

Progestagens inhibit growth of endometrial cancer cells in vivo and in vitro, and also are reported to inhibit endometrial cancer cell invasion. The progesterone receptor (PR) isotypes PRA and PRB have different transcriptional activity. There are indications that relative over expression of PRB could lead to development of a more invasive phenotype in endometrial cancer. To study the effect of progestagens and the two PR isotypes on tumor dissemination, in vitro and in vivo models should be applied. The Ishikawa endometrial cancer cell line (clone 3H12) was transfected to stably express a high level of human PRB (hPRB), which resulted in the PRB-1 sub-cell line. Ovariectomized athymic NMRI nu/nu mice were injected intraperitoneally with these PRB-1 cells. After 3, 5 and 10 weeks, the animals were sacrificed. Spread of PRB-1 cells in and outside the peritoneal cavity was studied macroscopically and microscopically, and also by PCR detection. After 10 weeks, the PRB-1 cells had formed extensive tumor mass in the peritoneal cavity. Also, cells could be detected outside the peritoneal cavity, indicating metastatic ability of these cells. The present study describes an in vivo model that can provide a valuable tool in studying the influence of progestagens and the two PR isotypes on endometrial cancer cell invasion and metastasis.
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PMID:Progesterone receptors in endometrial cancer invasion and metastasis: development of a mouse model. 1466 70

The nuclear progesterone receptor (PR), which is expressed as two proteins with different functions (PRA and PRB), is expressed in the normal endometrium and endometrial cancer. Our previous work has shown that there is a disruption to the relative PR isoform expression in progression to malignancy in endometrial cancer in which expression of a single isoform is common. A consistent feature in these studies was discrete punctate distribution of PRA and PRB in the nuclei of endometrial cancer cells. In this study PRA and PRB distribution within the nucleus was examined in vivo in the normal endometrium during the menstrual cycle, and in endometrial cancer, by dual immunofluorescence and confocal microscopy using cohorts in which PRA and PRB expression levels have previously been characterized. In the normal endometrium, PR was distributed evenly within the nucleus and also localized in discrete subnuclear foci. In the proliferative phase, even PR distribution was predominant and both PR isoforms were colocated and distributed evenly. In the secretory phase, there was a marked increase in the proportion of nuclei containing PR distributed into discrete foci, and PRB was the predominant isoform in nuclear foci. There was an inverse relationship between even and focal PR distribution in the menstrual cycle, suggesting that hormonal fluctuations were involved in movement of PR into focal nuclear locations. In endometrial cancers colocalization of PRA and PRB was infrequent, and there was no relationship between even and focal PR isoform distribution, unlike the normal endometrium. PRA was predominantly evenly distributed in endometrial cancers, whereas PRB was focal. Even PRB distribution in endometrial cancer was not often noted. Multivariate analysis showed that PRA expression was highly predictive of even nuclear distribution in endometrial cancers and PRB expression of distribution into foci, and these associations were independent of total PRA and PRB levels. Nuclear distribution of PR isoforms was associated with clinical grade, where tumors of high grade had significantly fewer nuclei containing even PRA distribution and focal PRB distribution, compared with tumors of low grade. In the normal endometrium, localization of PR into nuclear foci coincides with high progesterone levels, suggesting that altered intranuclear PR distribution is hormonally regulated. Nuclear distribution may be an important component of gene regulation in target tissues, and disruptions in PR distribution in endometrial cancer could affect the function of PR and contribute to aberrant hormonal responses.
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PMID:Subnuclear distribution of progesterone receptors A and B in normal and malignant endometrium. 1500 45

Previous studies showed that progesterone receptor (PR), one of the hormone receptor superfamily, was only connected with the sex-correlated cancers such as breast cancer, endometrial cancer, prostate cancer, etc. This article deals with the PR gene in leukemia. We investigated the methylation status and the expression of the two different PR isoforms, PRA and PRB, in three leukemia cancer cell lines using methylation-specific polymerase chain reaction (MSP-PCR) and reverse transcription-PCR. The correlation of PR methylation and expression together with DNA methyltransferase (DNMT1) was further studied. We found that DNMT1 is required to maintain CpG methylation and aberrant gene silencing of PR gene in human leukemia cancer cells. The activity of 5-aza-2'-deoxycytidine in demethylation and gene reactivation may be through depleting cellular DNMT1 levels. In addition, extensive methylation of PRA and PRB was also observed in leukemia samples. Our results suggest that PR CpG island aberrant hypermethylation could be one molecular and genetic alteration in leukemia.
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PMID:Progesterone receptor gene inactivation and CpG island hypermethylation in human leukemia cancer cells. 1517 46

In endometrial cancer, decreased expression of progesterone receptor (PR) isotypes A and B (PRA and PRB) is a feature of poorly differentiated tumours. In distant metastases, PRB is the predominantly expressed isotype and endometrial cancer cells that express PRB have been observed to be more invasive. Furthermore, PRB-associated in vitro invasion is markedly inhibited by progestagens. In the present study, ovariectomized mice were injected intraperitoneally with Ishikawa endometrial cancer cells that express only PRA, only PRB, both PRA and PRB, or no PR. Half of the mice were substituted with medroxyprogesterone acetate (MPA). After ten weeks, growth and spread of the cancer cells were examined macroscopically, microscopically, and by PCR detection. Without MPA substitution, cells that express only PRB were found to be the most proliferative and migrative, while cells that express only PRA, both receptor isotypes, or no PR, showed minimal growth and spread. MPA appeared to inhibit growth and spread of PR-positive cells. Surprisingly, when mice that were inoculated with PR-negative cells were substituted with MPA, this resulted in massive abdominal tumour growth. These results provide further evidence that over-expression of PRB in endometrial cancer contributes to the development of a more aggressive phenotype. MPA inhibits tumour growth and spread of PR-positive cells, but can also have an indirectly stimulating effect on PR-negative tumour cells, probably through a host-mediated response.
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PMID:Progesterone receptor A and B expression and progestagen treatment in growth and spread of endometrial cancer cells in nude mice. 1561 56

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


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