Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen independence is the major cause of endocrine therapy failure in advanced prostate cancer (PC). To examine the effects of human androgen receptor (AR) expression on growth of human PC cells, transfection of full-length AR cDNA in an androgen-insensitive human prostatic adenocarcinoma cell line (DU145) was performed. Transcriptional activity of AR was confirmed by the MMTV luciferase assay and AR expression was assessed by reverse transcriptase polymerase chain reaction, Western blotting, and immunocytochemistry. Two stable transfectant cell lines expressing functional AR were established and passaged over 60 times. Under standard culture conditions, AR expression in transfected cells was predominantly cytoplasmic. Exposure to dihydrotestosterone (DHT; 60 pM-10 nM) resulted in a rapid (maximal at 30 minutes) translocation of AR to the nucleus. Treatment with DHT (5 nM) caused a significant reduction in cell-cell adhesion and aggregation accompanied by a decrease in E-cadherin expression. This was associated with up to 40% inhibition of proliferation and approximately two-fold increase in apoptosis. These results suggest that gene transfer-mediated AR expression in DU145 cells confers sensitivity to DHT, modulates cell-cell adhesion through E-cadherin, and suppresses cell growth by inhibiting proliferation and promoting apoptosis. This provides amodelfor studies ofAR-regulated cell signalling and identification of novel androgen-regulated genes in PC.
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PMID:Ligand activation of the androgen receptor downregulates E-cadherin-mediated cell adhesion and promotes apoptosis of prostatic cancer cells. 1451 6

The molecular genetics of prostate cancer, the second most common cause of cancer-related death in men, is poorly understood. Inherited factors are believed to account for 42% of the risk of prostate cancer, and although multiple chromosomal loci of susceptibility have been identified, the target genes for these loci have not been well defined. Its heterogeneous nature suggests that the predisposition to prostate cancer may involve multiple genes and variable phenotypic expression. Genes that have been found to play a role in progression of prostate cancer include GSTP1 and PTEN, as well as the androgen receptor (AR) gene. Evidence suggests that the AR signaling pathway can be activated by other ligands when androgen levels are low. Recent findings have also implicated Kruppel-like factor 6 (KFL6), E-cadherin, the p40 subunit of eukaryotic translation initiation factor (eIF3-p40), and Elongin C, but confirmatory evidence is required to clarify the roles of these factors. Technologic advances, such as complementary DNA and tissue microarrays, have facilitated identification of genetic alterations and investigations of their function, but improved tools for searching and analyzing genes are still needed.
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PMID:The molecular genetics of prostate cancer. 1460 12

Loss of function of the E-cadherin gene (CDH1) has been linked with diffuse gastric cancer susceptibility, and germline inactivating mutations in CDH1 characterise the hereditary diffuse gastric cancer (HDGC) syndrome. Hypermethylation in the CDH1 promoter region is a frequent phenomenon in poorly differentiated, diffuse gastric carcinomas and it was identified as the main mechanism for the inactivation of the remaining wild-type allele in HDGC cases. Specific criteria are used to identify patients with suspected HDGC and who should be investigated for CDH1 germline mutations. Accurate screening is mandatory for unaffected carriers of CDH1 mutations and selected high-risk individuals could be considered for prophylactic gastrectomy. Also, germline CDH1 mutations may predispose to lobular breast carcinoma and prostate cancer. Germline CDH1 mutations are not always detectable in patients who meet the HDGC criteria and the aetiological role of this gene is still under investigation. Families without recognised inactivating CDH1 mutations may have undisclosed CDH1 mutations or mutations in its regulatory sequences or germline mutations in unidentified genes that also contribute to the disease. In recent years, several germline missense CDH1 mutations have been identified, some of which showed a marked negative influence on E-cadherin function in experimental models. CDH1 promoter hypermethylation seems a key event in the carcinogenetic process of poorly differentiated, diffuse gastric cancer and it deserves further investigation as a new target for anticancer therapies with demethylating agents.
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PMID:The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. 1463 Jun 73

Cell adhesion molecules (CAMs) play an important role in cancer metastasis by facilitating attachment to vascular endothelia, invasion and spread into secondary tissue sites. We have shown that activated eosinophils (EosA) inhibited the growth of prostate cancer (Pca) cells in vitro. In the present study, we examined the ability of EosA 24 hr conditioned supernatants (EosAcs) to modulate the expression of ICAM-1, VCAM-1, ELAM-1, E-cadherin and N-cadherin expression on human Pca cell lines, Du-145 and PC-3 by flow cytometry. TNF-alpha, IL-10 and IL-12 were also evaluated. ICAM-1, expressed on PC-3 and DU 145 cells, was enhanced by TNF-alpha and IL-10. ELAM-1 was present on DU 145 cells but absent on PC-3. TNF-alpha and IL-10 enhanced ELAM-1 on DU 145, but EosA 24 hr supematants failed to do so. All three cytokines, namely IL-10, IL-12 and TNF-alpha-induced ELAM-1 on PC-3 tumor cells. Although VCAM-1 was absent on DU 145 and PC-3 cells, it was expressed on DU-145 cells after exposure to EosA: tumor cell co-cultures, and was expressed on PC-3 following exposure to IL-10 and IL-12. N-cadherin and E-cadherin were both expressed on DU-145. While N-cadherin was expressed on PC-3 cells, E-cadherin was not. N-cadherin was enhanced on DU-145 and PC-3 cells following exposure to EosA co-culture and upregulated on PC-3 by IL-10 and EosA 24 hr supernatants, but decreased by IL-12. E-cadherin was up-regulated on DU 145 cells following co-culture with EosA and was induced on PC-3 by IL-10 and IL-12, but not by EosA co-culture and 24 hr supematants. In conclusion, inflammatory and non-inflammatory cytokines modulate CAM expression on Pca cells; EosA and EosA 24 hr supernatants also exerted modulatory activity of CAM expression. Most significantly, the metastasis suppressor molecule, E-cadherin was enhanced on DU 145 cells by EosA and induced on PC-3 by IL-10 and IL-12 both of which are produced by EosA. This suggests potential use of these cytokines in immunotherapeutic strategies for prostate cancer and its metastasis.
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PMID:Activated eosinophils upregulate the metastasis suppressor molecule E-cadherin on prostate tumor cells. 1468 82

A cDNA clone of 1.1 kb encoding a 108-aa polypeptide was isolated from a human pituitary cDNA library by expression cloning. This protein was named tumor differentiation factor (TDF). The recombinant TDF protein and a 20-aa peptide, P1, selected from the ORF of the gene, induced morphological and biochemical changes consistent with differentiation of human breast and prostate cancer cells. Fibroblast, kidney, hepatoma, and leukemic lymphocytic cell lines were unaffected. Breast and prostate cancer cells aggregated in spheroid-like structures within 24 h of exposure to TDF. This effect was abrogated by a specific affinity-purified rabbit polyclonal anti-P1 Ab. E-cadherin expression was increased in a dose-dependent manner by TDF. Treatment of MCF7 cells with TDF led to production of a lactalbumin-related protein. Peptide P1 significantly decreased the growth of androgen-independent DU145 prostate cancer in severe combined immunodeficient mice. The presence of TDF protein in human sera was detected by the anti-P1 Ab, suggesting a role of TDF in endocrine metabolism. The fact that all activities of TDF can be mimicked by a peptide derived from the encoding TDF sequence opens the possibility of therapeutic applications.
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PMID:A pituitary gene encodes a protein that produces differentiation of breast and prostate cancer cells. 1474 5

The E-cadherin (CDH1) gene has been associated with prostate carcinogenesis. The C/A polymorphism--160 base pairs relative to the transcription start site has been shown to decrease gene transcription. We analyzed the association between this polymorphism and the risk of sporadic, familial (2 close relatives) and hereditary (3 or more close relatives) prostate cancer. We combined data from 3 population-based epidemiologic studies in Sweden encompassing altogether 1,036 prostate cancer cases and 669 controls that were genotyped for the short nucleotide polymorphism. Odds ratios with 95% confidence intervals were estimated through unconditional logistic regression. We found no significant association between the A-allele and sporadic (OR = 1.0; 95% CI = 0.8-1.2) or familial (OR = 1.4; 95% CI = 0.9-2.2) prostate cancer. In contrast, risk of hereditary cancer was increased among heterozygote CA carriers (OR = 1.7; 95% CI = 1.0-2.7) and particularly among homozygote AA carriers (OR = 2.6; 95% CI = 1.4-4.9). Our data indicate that the -160 single nucleotide polymorphism in CDH1 is a low-penetrant prostate cancer susceptibility gene that might explain a proportion of familial and notably hereditary prostate cancer.
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PMID:-160C/A polymorphism in the E-cadherin gene promoter and risk of hereditary, familial and sporadic prostate cancer. 1496 71

The role(s) of E-cadherin in tumor progression, invasion, and metastasis remains somewhat enigmatic. In order to investigate various aspects of E-cadherin biological activity, particularly in prostate cancer progression, our laboratory cloned unique subpopulations of the heterogeneous DU145 human prostatic carcinoma cell line and characterized their distinct biological functions. The data revealed that the highly invasive, fibroblastic-like subpopulation of DU145 cells (designated DU145-F) expressed less than 0.1-fold of E-cadherin protein when compared to the parental DU145 or the poorly invasive DU145 cells (designated DU145-E). Experimental disruption of E-cadherin function stimulated migration and invasion of DU145-E and other E-cadherin-positive prostate cancer cell lines, but did not affect the fibroblastic-like DU145-F subpopulation. Within the medium of parental DU145 cells, the presence of an 80 kDa E-cadherin fragment was detected. Subsequent functional analyses revealed the stimulatory effect of this fragment on the migratory and invasive capability of E-cadherin-positive cells. These results suggest that E-cadherin plays an important role in regulating the invasive potential of prostate cancer cells through an unique paracrine mechanism.
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PMID:Dual roles of E-cadherin in prostate cancer invasion. 1499 57

Gene methylation is an important molecular event in prostate carcinogenesis that may have diagnostic and prognostic significance. We evaluated the methylation status of eight genes implicated in prostate carcinogenesis. DNA was extracted from archived paraffin-embedded tumor blocks from 90 prostate cancer patients. Gene methylation status of eight genes (GSTP1, RASSF1A, RARbeta2, CD44, EDNRB, E-cadherin, Annexin-2, and Caveolin-1) was determined using real-time methylation-sensitive PCR techniques. Differences in gene methylation among race, tumor grade and disease stage were evaluated by chi-square test. Of the eight genes, GSTP1, RASSF1A, and RARbeta2 methylation was highly prevalent across tumors (>60% for all three genes) whereas CD44, E-cadherin and EDNRB methylation was less prevalent (33, 24 and 29%, respectively). Annexin-2 and Caveolin-1 were not methylated in any of the tumors examined. Methylation of RARbeta2, CD44 and E-cadherin was correlated with tumor grade but not stage. Interestingly, methylation of EDNRB, a gene involved in angiogenesis, was correlated with stage of disease but not tumor grade. With the possible exception of CD44, we did not observe differences in gene methylation between racial categories for the genes under study. In summary, our data suggest that evaluation of the methylation of a panel of genes may have diagnostic and prognostic utility in prostate cancer.
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PMID:A survey of gene-specific methylation in human prostate cancer among black and white men. 1503 50

Radical prostatectomy as a primary treatment for clinically localized prostate cancer has increased dramatically over the past decade due to prostate-specific antigen (PSA) screening and the awareness of the increased incidence of localized disease. Despite the stage migration to increase clinically localized disease, there are still vast numbers of men who harbor occult extraprostatic extension and develop recurrence after surgery. The study of molecular markers in the blood or tissue of surgical patients prior to treatment, called " molecular staging, " is the focus of this review. The reverse transcriptase- polymerase chain reaction (RT-PCR) test for PSA gene expression in peripheral blood or bone marrow has received considerable attention since its first report in 1992. The test detects messenger RNA species for prostate-specific/abundant genes such as PSA and prostate-specific membrane antigen. These messenger RNAs were not detected in normal blood or bone marrow, but were detected in some prostate cancer patients presumably due to circulating prostatic epithelial cells. These prostate epithelial cells are thought to be occult metastases cells, and early studies correlated a positive RT-PCR test with surgical pathology adverse features such as positive margins. Despite the many studies over the past few years, there have been inconsistent results, and the most recent studies have not been able to confirm clinical utility. Bone marrow RT-PCR has been more promising; however, it is still a research tool that needs further study. The study of molecular markers in tissue material, ie, prostate biopsy samples prior to radical prostatectomy, is problematic due to the sampling error inherent in a multifocal heterogeneous tumor such as prostate cancer. The tumor suppressor proteins p53 and p27, Bcl-2 oncoprotein, Ki-67 proliferation index protein, E-cadherin, and microvessel density have been assessed in preradical prostatectomy needle biopsy. Results have been conflicting, and none are yet accepted as a clinically useful marker. Current and future work is focusing on analysis of multiple gene expressions or proteins simultaneously via gene chip or proteomics technology. While these expression profiles might be of value in whole prostate surgical specimens where tissues are well characterized, it is unclear how this new technology will be applied to the needle biopsy samples. Although molecular staging of radical prostatectomy patients has been under study for a decade, all assays remain research tools. Still, this area holds great promise for improving the accuracy of staging and providing a more accurate prognosis of individual men with clinically localized prostate cancer.
Clin Prostate Cancer 2002 Jun
PMID:Molecular markers in prostate cancer: the role in preoperative staging. 1504 12

Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (>4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8-32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P = 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.
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PMID:Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. 1512 78


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