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)

Recent advances in molecular biology have allowed us to understand that it is the accumulation of genetic alterations which leads to each step of tumorigenesis. What the specific alterations may be, however, often varies with each neoplasm. Prostate cancer is somewhat unique in its presentation to the pathologist of a bewildering array of histologies difficult to assign to diagnostic categories and contributing to misinterpretations of underlying molecular events. As with any malignancy, it is of utmost importance to thoroughly analyze and record the genetic aberrations found in prostate cancer with the objective of correlation to the pathology and natural history of the disease. Multiple oncogenes and tumor suppressor genes have been investigated in both clinical and latent cancer using conventional mutational analyses. To probe deeper into these genes and to uncover novel molecular events, genomic tumor DNA were examined using restriction landmark genomic scanning (RLGS), a method which allows the identification and comparison of specific genetic alterations within large segments and multiple samples of DNA at a time. This article reviews what has been identified based on numerous molecular studies, focusing on the genetic alterations peculiar to human prostate cancer.
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PMID:Genetic changes in prostate cancer. 941 32

We have generated a transgenic mouse model in which female mice develop ductal mammary adenocarcinomas and male mice develop prostatic adenocarcinomas by using a transgene containing the hormone-responsive rat prostatic steroid binding protein 5' flanking region C3(1) fused to the simian virus 40 (SV40) large T antigen. We have identified some genetic alterations during mammary and prostate tumor progression: (i) p53 is functionally inactivated during mammary cancer development without p53 mutations; (ii) Alterations in apoptosis during mammary tumor progression are p53 and bcl-2 independent; (iii) Ha-ras mutations occur early in the development of prostate cancer. This unique animal model offers the opportunity to study multistep tumorigenesis in these organs.
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PMID:Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model. 945 74

Synthesis of nitric oxide (NO) has been shown in the glandular epithelium of human prostate, with highest levels in the peripheral zone. This location is believed to be the main source of prostatic cancer. The ability of stromal cells to produce NO may contribute to the malignant process. Since solid tumours are prone to hypoxia and malignant progression, experiments were undertaken to test the effect of respiratory block on the induction of nitric oxide synthase (NOS) by a Dunning rat prostatic epithelial line. A metastatic phenotype (Mat-LyLu) was treated in vitro with brief exposure to cyanide in order to mimic transient hypoxic stress. NADPH-diaphorase activities in paraformaldehyde-fixed cells was used to follow the expression of NOS. NADPH-diaphorase activity was found to be inducible by a range of factors, including mechanical damage and infection of cultures. Cyanide induced a dose-dependent staining that was statistically greater than in untreated cells. Consistent with diaphorase staining being a marker for the inducible isoform of NOS (iNOS), induction and enhancement of staining, respectively, was observed in response to treatment with lipopolysaccharide or withdrawal of dexamethasone supplement. Results demonstrate that prostatic epithelia can be triggered in culture to express iNOS by transient oxidative stress in the form of respiratory poisoning by NaCN. Paradoxically, nitric oxide production by epithelia within hypoxic zones of solid tumours may contribute to the promotion and/or inhibition of tumorigenesis.
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PMID:Transient block of respiratory chain by cyanide triggers NADPH-diaphorase activity (a marker for nitric oxide synthase) in Dunning rat prostatic epithelium. 945 79

Prostate cancer (PCA) is the most common nonskin malignancy and the second leading cause of cancer deaths in United States males. One practical and translational approach to control PCA is to define a mechanism-based anticarcinogenic agent(s). Recently, we showed that silymarin, a flavonoid antioxidant isolated from milk thistle, possesses exceptionally high to complete protective effects against experimentally induced tumorigenesis. Because the epidermal growth factor receptor (erbB1) and other members of the erbB family have been shown to play important roles in human PCA, efforts should be directed to identify inhibitors of this pathway for PCA intervention. In this study, we assessed whether silymarin inhibits erbB1 activation and associated downstream events and modulates cell cycle regulatory proteins and progression, leading to growth inhibition of human prostate carcinoma DU145 cells. Treatment of serum-starved cells with silymarin resulted in a significant inhibition of transforming growth factor alpha-mediated activation of erbB1 but no change in its protein levels. Silymarin treatment of cells also resulted in a significant decrease in tyrosine phosphorylation of an immediate downstream target of erbB1, the adapter protein SHC, together with a decrease in its binding to erbB1. In the studies analyzing cell cycle regulatory molecules, silymarin treatment of cells also resulted in a significant induction of cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27, concomitant with a significant decrease in CDK4 expression, but no change in the levels of CDK2 and CDK6 and their associated cyclins E and D1, respectively. Cells treated with silymarin also showed an increased binding of CDKIs with CDKs, together with a marked decrease in the kinase activity of CDKs and associated cyclins. In additional studies, treatment of cells grown in 10% serum with anti-epidermal growth factor receptor monoclonal antibody clone 225 or different doses of silymarin also resulted in significant inhibition of constitutive tyrosine phosphorylation of both erbB1 and SHC but no change in their protein levels. Furthermore, whereas silymarin treatment resulted in a significant increase in the protein levels of both Cip1/p21 and Kip1/p27, monoclonal antibody 225 showed an increase only in Kip1/p27. These findings suggest that silymarin also inhibits constitutive activation of erbB1 and that the observed effect of silymarin on an increase in CDKI protein levels is mediated via inhibition of erbB1 activation only in the case of Kip1/p27; however, additional pathways independent of inhibition of erbB1 activation are possibly responsible for the silymarin-caused increase in Cip1/p21 in DU145 cells. In other studies, silymarin treatment also induced a G1 arrest in the cell cycle progression of DU145 cells and resulted in a highly significant to complete inhibition of both anchorage-dependent and anchorage-independent growth of DU145 cells in a dose- and time-dependent manner. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against PCA and that this effect is likely to involve impairment of erbB1-SHC-mediated signaling pathway, induction of CDKIs, and a resultant G1 arrest.
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PMID:A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. 958 34

Deletions involving chromosome 10q23 occur frequently in prostatic carcinomas. Recently, a novel tumour suppressor gene, PTEN, mapping to this interval, has been identified. Mutation or deletion of PTEN has been observed in a proportion of prostate cancer cell lines; however, primary prostate carcinomas have not been studied. We have investigated the involvement of PTEN in primary prostatic adenocarcinomas using a panel of 51 matched normal and prostate tumour DNAs. We first determined the proportion of tumours with allele loss at loci in 10q23 which span the region containing the PTEN gene. Our results show that LOH involving 10q23 is common in primary prostate carcinomas. Twenty-five of 51 (49%) tumours showed loss of heterozygosity (LOH) over the region spanning the PTEN locus. We next directly analysed the PTEN gene for mutations of the coding region using single strand conformation polymorphism (SSCP) and sequence analyses. Of those tumours with LOH, only a single tumour was found to carry a missense mutation in PTEN. No mutations in PTEN were identified in tumours without LOH. Our results suggest either that mutation of PTEN is a late event in prostate tumorigenesis, or that another tumour suppressor gene important in prostate cancer may lie close to PTEN in 10q23.
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PMID:Analysis of PTEN and the 10q23 region in primary prostate carcinomas. 958 22

Fibroblast growth factor (FGF) 8, also known as androgen-induced growth factor, was originally isolated from an androgen-dependent mouse mammary Shionogi carcinoma SC-3 cell line, in which it was shown to have androgen-regulated properties. We previously demonstrated that Fgf 8 transcripts were detected in several human prostate and breast cancer cell lines and that recombinant FGF 8 was mitogenic to an androgen-sensitive prostate cancer LNCaP cell line. In this study, to characterize the roles of FGF 8 in clinical hormone-responsive cancers, we established a monoclonal antibody against FGF 8. In Western blots, this antibody specifically interacted with a FGF 8b isoform that was identical between mouse and human but was not identical to other murine 8a and 8c isoforms. In a cell growth assay using SC-3 cells, the newly established anti-FGF 8 antibody blocked androgen- and FGF 8-stimulated growth but not basic FGF-stimulated growth. Immunohistochemical analyses by use of the established anti-FGF 8 antibody demonstrated that FGF 8 was frequently expressed in human prostate cancers, appearing in 40 of 43 cases (93%), whereas both prostatic hyperplasia specimens and normal prostate tissues included in biopsy specimens were negative for FGF 8 expression. On the other hand, FGF 8 was detected in normal ductal and lobular epithelial cells in breast tissues. FGF 8 was also frequently expressed in various breast diseases, including fibroadenomas (5 of 5 cases, 100%), intraductal papillomas (3 of 3 cases, 100%), ductal hyperplasias (3 of 6 cases, 50%), and breast cancers (8 of 12 cases, 67%). Androgen receptors were also immunohistochemically detected in FGF 8-positive prostate cancers (40 of 40 cases, 100%) and FGF 8-positive breast diseases (17 of 19 cases, 89%). These findings strongly suggest that FGF 8 is involved in hormone-related tumorigenesis of the prostate and breast.
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PMID:High frequency of fibroblast growth factor (FGF) 8 expression in clinical prostate cancers and breast tissues, immunohistochemically demonstrated by a newly established neutralizing monoclonal antibody against FGF 8. 960 40

Prostate cancer is a major medical problem that is expected to affect over 300,000 American men and cause over 40,000 deaths in 1997. Despite its widespread prevalence and because of the difficulties in clinical diagnosis and treatment of the disease, the etiological mechanism underlying prostate carcinogenesis remains poorly understood. Elucidation of the mechanism of prostate tumorigenesis has been slowed by a lack of tumor tissues and the limited number of human cell lines available for study. In vitro human cell models to study the molecular biology of prostate cancer progression are urgently needed. Normal human prostate cells require immortalization to provide a practical system for transformation studies. Neoplastic transformation of human prostate epithelial cells in culture has been achieved recently in a stepwise fashion--immortalization of primary cells in culture and conversion of the immortalized cells to a tumorigenic state. Reviewed here are the steps involved in the neoplastic transformation of human prostate cells. To provide an insight into the molecular and genetic mechanisms involved in the conversion of normal cells to a neoplastic state of growth, the authors have attempted to put into perspective the history of human prostate epithelial cell transformation by a combination of carcinogenic agents, and to discuss the current state-of-the-art in transformation of human prostate epithelial cells in culture.
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PMID:Human prostate carcinogenesis. 962 52

Prostatic carcinogenesis is a multistep process with well-documented stages. Although prostate cancer is a major cause of mortality many small tumor foci never progress to form clinically significant disease, indicating that the disease process may be regulated at more than one level. Carcinogenesis is accompanied by increasing genetic damage to prostatic epithelial cells, however the pattern of genetic lesions is inconsistent. The differentiation of stromal cells surrounding tumors is more fibroblastic and less muscular than in normal prostate. The present communication reviews the roles of both genetic and, stromally derived, epigenetic effects on prostatic tumorigenesis.
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PMID:Genetic and epigenetic influences in prostatic carcinogenesis (review). 962 1

Prostate cancer progresses from a localized disease to a widely disseminated malignancy. Each step along this progression pathway involves multiple genetic alterations that impart a survival advantage to the tumor cell over its normal counterparts and may confer resistance to therapy. Because metastatic prostate cancer is one of the most therapy-resistant human neoplasms, we studied the expression of certain molecular determinants of drug resistance in the context of tumor progression. Paraffin-embedded formalin-fixed resected prostates were chosen based on Gleason grade and surgical stage. Immunohistochemistry was used to detect the expression of multidrug resistance protein (MRP), topoisomerase II alpha, p53, glutathione S-transferase pi, Bcl-2, and P-glycoprotein in these specimens. We found that all of the proteins were expressed in resected prostate except for P-glycoprotein. The expression of MRP, topoisomerase II alpha, p53, and Bcl-2 increased with the Gleason grade. In addition, the expression of MRP, topoisomerase II alpha, and p53 increased with the surgical stage. In contrast, the glutathione S-transferase pi and Bcl-2 expression decreased with the increasing surgical stage. Stage was the strongest indicator of protein expression. These results suggest that drug resistance gene products are expressed in prostate cancer at the time of surgical resection. Thus, although the emergence of the "pan-resistance" phenotype in prostate cancer may partly be a function of the selection pressure exerted by therapeutic interventions, certain determinants of chemoresistance may be caused by genetic changes accompanying tumorigenesis.
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PMID:The expression of drug resistance gene products during the progression of human prostate cancer. 962 55

Beta-catenin plays essential roles in both intercellular adhesion and signal transduction. As a signaling molecule, beta-catenin supplies an activating domain to the T-cell factor/lymphoid enhancer-binding factor family of DNA-binding proteins and activates gene transcription. Posttranslational stabilization of beta-catenin, leading to elevated protein levels and constitutive gene activation, has been proposed as an important step in oncogenesis. Stabilization of beta-catenin can occur through mutation to highly conserved amino acids encoded in exon 3 of the beta-catenin gene (CTNNB1). To determine whether this pathway of malignant transformation is important in prostate cancer, we analyzed 104 prostate cancer tissue specimens, 4 prostate cancer cell lines, and 3 prostate tumor xenografts for activating mutations in exon 3 of CTNNB1. Mutations were detected in 5 of the 104 prostate cancer tissue samples. Four of the five mutations involved serine or threonine residues implicated in the degradation of beta-catenin. A fifth tumor had a mutation at codon 32, changing a highly conserved aspartic acid to a tyrosine. Mutational analysis of multiple regions from several tumor samples showed that the beta-catenin mutations were present focally and therefore may occur during tumor progression.
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PMID:Beta-catenin mutations in human prostate cancer. 963 71


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