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)

Soy-based diets, rich in the isoflavones genistein and daidzein, are thought to protect against breast and prostate cancer. We used the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis animal model to test the effectiveness of these two isoflavones as chemopreventive agents. Each isoflavone was injected daily into 35-day-old rats for six months while we monitored the animals' body weight and mammary tumor appearance. Genistein was effective in reducing tumor multiplicity, but it reduced tumor incidence only marginally. Daidzein was less effective in reducing both tumor incidence and multiplicity. To investigate genistein's mechanism of action, we determined the topoisomerase II (topo II) activity and detected the phosphotyrosine-containing peptides in the extracts of mammary tissues isolated from control and isoflavone-treated animals. Mammary tumors contained over 60-fold higher topo II enzymatic activity than the mammary glands. Similarly, more tyrosine phosphopeptides were detectable in mammary tumors than in mammary glands. Tissue samples from genistein treated animals contained similar topo II and protein tyrosine kinase (PTK) activities as the control group. These data suggest that mammary tumorigenesis is accompanied by an extensive increase in topo II and PTK activities. The mechanism of chemoprevention by genistein, however, is independent of topo II or PTK inhibition.
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PMID:Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by the soybean isoflavones. 904 3

Genetic alterations, such as mutation, methylation and aneuploidy, are thought to underlie the multistep genesis and progression of many human cancers. However, the genetic events occurring in prostatic oncogenesis are still relatively poorly understood. This is especially so in early-stage tumours, in which mutations of known oncogenes or tumour-suppressor genes appear to be quite infrequent. Allelic losses of chromosome arms 7q, 8p, 10, 16q and 18q suggest the involvement of novel suppressor loci on these chromosomes; allelic losses of chromosome arm 8p are especially frequent and may be detected even in early-stage tumours. We have used a positional approach to seek novel genetic targets in prostate cancer, including allelic-loss mapping of chromosome 8p and physical mapping of chromosome band 8p22 around the MSR gene. A homozygous somatic deletion in one prostatic nodal metastasis was mapped in this region and spanned 730-970 kb. This region was then examined in detail for expressed sequences. One novel gene, called N33, was found to be silenced by a methylation mechanism in most colon cancer cell lines and some primary colorectal tumours. Characterization of additional chromosome 8p22 candidates is in progress.
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PMID:Tumour-suppressor genes in prostatic oncogenesis: a positional approach. 908 70

Cadherins are a family of calcium-dependent cell-cell adhesion molecules involved in cell-cell aggregation and morphoregulatory cell function. Dysfunction of the cadherin pathway is involved in tumour invasiveness and disease progression for a variety of carcinomas. E-cadherin is a prognostic marker in prostatic cancer, based on the correlation of the grade of E-cadherin expression and tumour grade, stage, metastasis and survival, as well as recurrence after radical prostatectomy. P-cadherin was shown to be lost in all prostatic cancers, although this most likely reflects loss of the basal cell population rather than a transcriptional down-regulation, suggesting that loss of P-cadherin expression is an early event in the tumorigenesis of prostatic carcinomas. Catenins, particularly alpha-catenin, also play an important role in the dysfunction of the cell adhesion complex. Mechanisms of inactivation of the cadherin-catenin pathway include LOH, gene deletions and gene promoter hypermethylation. Therapeutic strategies have been investigated in tumour models, i.e. the use of demethylating agents for the hypermethylated promoter region of E-cadherin or gene transfer in PC-3 cells with homozygous deletion of the alpha-catenin gene. The complexity of neoplastic changes cannot be explained by alterations of cell adhesion molecules alone; but as demonstrated, cadherins and catenins play an important role in this process.
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PMID:The cadherin cell-cell adhesion pathway in prostate cancer progression. 908 71

Prostate cancer is the most commonly diagnosed male malignancy in western countries. Recent work in cell biology and molecular cytogenetics has led to a large amount of data on chromosomal abnormalities in prostatic tumors. A highlight of the literature describing both classical and molecular cytogenetic studies of prostate cancer is presented. By conventional cytogenetics, predominant changes included gain of chromosome 7, loss of Y, deletions of 7q and 10q, and the appearance of double minutes. Using fluorescence in situ hybridization, predominant changes included gains of chromosomes 1, 7, 8, 8q sequences, 17, X and Y, and loss of chromosomes 1, 7, 8, 8p sequences, 10, 10q, 16q and 17q sequences, 17 and Y. Newly defined sites by comparative genomic hybridization included loss of genetic material on 2q, 5q, 6q, 9q, 13q, 15q, 17p, and 18q, and gains at 1q, 2p, 3q, 7q, 9q, 11p, 16p, 20, 22, and X. These data indicate that multiple non-random genomic sites are involved in prostate tumorigenesis. This wide and relatively recent gain of information is likely to provide key clues to the biologic basis of this disease.
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PMID:Cytogenetic studies in prostate cancer: are we making progress? 914 Apr 61

Transforming growth factor-beta (TGF-beta1) is a potent negative regulator of cell growth that transduces signals through interactions with type I and II receptors. Abnormal expression and mutational alterations of these receptors have been observed in several human malignancies. In this study, we investigated the expression of the two types of TGF-beta1 receptors, R-I and R-II, in a normal human prostate, primary prostate adenocarcinoma and lymph nodes with metastatic deposits. Expression of receptor proteins was examined by immunohistochemical analysis in paraffin-embedded prostatic tissue sections, and mRNA expression was determined by Northern blot and RT-PCR analysis. Uniformly strong immunoreactivity for both TGF-beta receptor proteins, R-I and R-II, was exclusively localized to the prostatic glandular epithelium of normal prostates. In contrast, tumor epithelial cells in primary and metastatic prostatic cancer specimens exhibited a weak heterogeneous immunoreactivity for both R-I and R-II receptors; 25% of primary prostatic tumors and 45% of the lymph nodes with metastases were totally negative for R-I and R-II expression, while the rest exhibited a significantly reduced immunoreactivity for both types of receptors compared to the normal prostate (p < 0.05). Moreover, there was a significant decrease in the expression of R-I and R-II mRNA, in all 20 primary prostatic tumors and 4 lymph nodes positive for metastases, indicating that the decreased protein expression was due to down-regulation of gene expression for the two receptors. Our findings imply that decreased expression of TGF-beta1 type I and type II receptors might be involved in prostate tumorigenesis.
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PMID:Down-regulation of protein and mRNA expression for transforming growth factor-beta (TGF-beta1) type I and type II receptors in human prostate cancer. 917 10

KLK1/tissue kallikrein is a member of a family of structurally related serine proteases which exhibit a diverse range of enzymic activities. Other members of this family of genes and the bradykinin (B2) receptor have been implicated in cancer processes. The KLK genes are expressed in various organs of the reproductive tract, including the prostate and uterus. In this study, we have examined whether KLK1/tissue kallikrein and the B2 receptor were both expressed in cancers emanating from these organs. We have shown that KLK1/tissue kallikrein and the B2 receptor are expressed, to varying degrees, in prostate disease and 2 human prostate cancer cell-lines, LNCaP and DU145. KLK1 is also expressed in a range of endometrial cancers, although at lower levels than that observed for normal human endometrial tissues. These findings suggest that a functional kallikrein-kinin system is present in prostate disease, in particular, which may be important in the process of tumorigenesis in this tissue.
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PMID:Tissue kallikrein and the bradykinin B2 receptor are expressed in endometrial and prostate cancers. 922 49

The possibility of maintaining and studying human prostatic cancers in an in vitro and in vivo environment has allowed the development of rare but essential tools to study many aspects of the biology of these cancers. Although none of the available models is perfect, the sum of the studies conducted with these models over more than 20 years constitutes the basis for major progress in our understanding of this disease. The most widely used cell lines (cultured in vitro) are PC-3, DU-145 and LNCaP. They are limited by the fact that they are essentially androgen-independent cell lines, derived from metastatic sites. Due to the slow growth of prostatic cancers, it is very difficult to obtain cancer cell lines which can be transplanted in immunodeficient animals (such as athymic mice) and only a few xenografts are currently available, some of which, like PCV-82, LuCaP 23, CWR-22, are androgen-dependent or sensitive. These models can be used to study host-tumour interactions as well as endocrinological interactions, stroma-tumour cell interactions, and to analyse molecular phenomena related to stages of hormone dependence and hormone resistance. In vitro and in vivo models of metastatic prostatic cancer have also been developed and appear to have a crucial impact on the understanding of metastatic mechanisms and new therapeutic approaches. This paper describes the main experimental models developed from human prostatic cancers, their main characteristics, their value compared to clinical cancers and some of the major studies conducted with these models. Due to the exponential progress in molecular biology techniques and oncogenetics, it appears essential to increase the number and diversity of experimental models of prostatic cancer in order to advance research concerning the crucial phenomena occurring during the course of this disease, from oncogenesis to currently incurable metastatic stages.
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PMID:[In vitro and in vivo models developed from human prostatic cancer]. 927 65

The molecular events underlying prostatic tumorigenesis remain incompletely understood. The application of cytogenetic, molecular genetic and molecular cytogenetic techniques have led to the identification of consistent genetic changes. This paper will discuss these techniques, review the genetic aberrations discovered, and consider how these aberrations contribute to our knowledge of the initiation, progression, metastatic spread and resistance to hormonal therapy of prostate cancer.
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PMID:The genetic analysis of prostate carcinoma. 929 80

Growth of prostatic epithelial cells is androgen-dependent; however, the mechanism of androgen action on cell growth is not well defined. We investigated whether androgen-dependent prostatic epithelial cell growth is mediated by androgen regulation of expression of genes controlling cell cycle progression. For this purpose, we used an androgen-dependent prostatic cancer cell line, LNCaP-FGC, as an in vitro model. We found that expression of CDK2 and CDK4 genes were up-regulated within hours of androgen treatment as detected in Northern and Western blot analyses. Kinase assay also confirmed that there was increased CDK2 kinase activity upon androgen stimulation. Moreover, androgen down-regulated expression of the cyclin-dependent kinase inhibitor p16 (MTS1, CDKN2) gene. The overall effects of these androgen actions result in an increased cyclin-dependent kinase activity and stimulation of the cell to enter S phase of the cell cycle, thereby enhancing cell proliferation. In contrast, an androgen-independent PC-3 cell line lost its response to androgen stimulation, and higher basal levels of CDK2, CDK4, and p16 genes were constitutively expressed in PC-3 cells. Collectively, these data suggest a possible signaling pathway of androgen in stimulating cell growth. These results also imply that in androgen-dependent prostate cancer, increased androgen receptor (AR) activity, resulting from AR gain-of-function mutations, AR gene amplification, or AR gene overexpression, malignantly stimulates proliferation of prostatic epithelial cells and constitutes one possible mechanism of androgen-dependent tumorigenesis.
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PMID:Regulation of androgen-dependent prostatic cancer cell growth: androgen regulation of CDK2, CDK4, and CKI p16 genes. 937 62

Only limited data are available on chromosomes specifically involved in the multistep tumorigenesis of prostate cancer. To investigate the cytogenetic status at different stages of prostatic tumor development, we have applied interphase in situ hybridization (ISH) with a set of (peri) centromeric DNA probes--specific for chromosomes 1, 7, 8, and Y--to routinely processed tissue sections of prostatic specimens from 75 different individuals. Our panel consisted of: 16 normal/benign prostatic hyperplasia specimens; 23 primary, localized, prostatic tumors (N0M0 stage); 20 regional lymph node metastases (M0 stage); and 16 distant metastases. Numerical aberrations of at least one chromosome were not observed in normal/benign prostatic hyperplasia cases, but were present in localized tumors (39%), regional lymph node metastases (40%), and distant metastases (69%). Within the different pTNM groups, we observed the following aberrations (listed, within each series, in decreasing order of frequency): -Y, +8, -8, +7 in primary tumors; +8, +7, -Y, +Y, -8 in regional lymph node metastases; and +8, +7, +1, -Y, -8 in distant metastases. In primary tumors, the number of aberrant cases increased significantly with local tumor stage (p < 0.05). A significant increase in gain of chromosome 8 was also observed (p < 0.02). Gain of chromosome 7 and/or 8 showed a significant increase with progression of local tumor stage (p < 0.02). Specific involvement of chromosome 8 was seen in bone metastases, but not in hematogenous metastases to other sites (p = 0.02). Comparative genomic hybridization analysis of these bone metastases disclosed centromere 8 gains as amplifications of the (whole) 8q arm, whereas centromeric loss appeared to be due to loss of 8p sequences. With progression toward metastatic disease, an accumulation of genetic changes was seen as exemplified by gain of chromosome 1, which was solely observed in distant metastases. With tumor progression, gain of chromosomes 7 and/or 8 significantly increased (p = 0.03), whereas the number of cases with aberrations of the Y chromosome did not change. Furthermore, ploidy status determined by ISH revealed a significant increase in the number of aneuploid cases along with advancement of pTNM stage (p = 0.04). Collectively, the data strongly suggest that: (a) gain of chromosome 7 and/or 8 sequences is implicated in prostatic tumor progression; (b) gain of chromosome 8 sequences is related to local tumor growth; (c) overrepresentation of 8q sequences, most likely by isochromosome 8q formation, is involved in metastatic spread to the bone; and (d) changes in the centromeric copy number, as detected by interphase ISH, might in some cases represent structural alterations, such as an isochromosome.
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PMID:Interphase cytogenetics of prostatic tumor progression: specific chromosomal abnormalities are involved in metastasis to the bone. 938 87


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