National Cancer Institute®
Last Modified: September 1, 2002
UI - 12161611
AU - Caldes T; de la Hoya M; Tosar A; Sulleiro S; Godino J; Ibanez D; Martin
TI - M; Perez-Segura P; Diaz-Rubio E A breast cancer family from Spain with germline mutations in both the BRCA1 and BRCA2 genes.
SO - J Med Genet 2002 Aug;39(8):e44
UI - 12114473
AU - Tulinius H; Olafsdottir GH; Sigvaldason H; Arason A; Barkardottir RB;
TI - Egilsson V; Ogmundsdottir HM; Tryggvadottir L; Gudlaugsdottir S; Eyfjord JE The effect of a single BRCA2 mutation on cancer in Iceland.
SO - J Med Genet 2002 Jul;39(7):457-62
AD - Icelandic Cancer Society, Reykjavik, Iceland University of Iceland, Reykjavik, Iceland. firstname.lastname@example.org
OBJECTIVE: To estimate the risk of malignant diseases in families of probands with the same mutation in the BRCA2 gene. DESIGN: A cohort study using record linkage of a breast cancer family resource and the Icelandic Cancer Registry. SETTING: Iceland. SUBJECTS: Families of 995 breast cancer patients, from which 887 were tested for a single founder 999del5 mutation; 90 had the mutation and 797 did not. RESULTS: Relatives of probands with the mutation had significantly increased relative risk (RR) of breast cancer. For first degree relatives, the RR was 7.55 (95% CI 6.04 to 9.03) but was 1.72 (95% CI 1.49 to 1.96) in first degree relatives of probands without the mutation. For prostate and ovarian cancer, the first and second degree relatives of probands with the mutation had a significantly increased RR, but in families of probands without the mutation no significant familial risk was found. CONCLUSIONS: The 999del5 mutation in the BRCA2 gene explains a substantial proportion of familial risk of breast cancer in Iceland, but significant familial risk remains in relatives of probands without the mutation. For prostate and ovarian cancer, the mutation accounts for most of the familiality observed in families of breast cancer patients.
UI - 11876548
AU - Kavantzas N; Agapitos E; Lazans AC; Pavlopoulos PM; Sofikitis N; Davaris
TI - P Nuclear/Nucleolar morphometry and DNA image cytometry as a combined diagnostic tool in pathology of prostatic carcinoma.
SO - J Exp Clin Cancer Res 2001 Dec;20(4):537-42
AD - Dept. of Pathology, Medical School, National University of Athens, Greece. email@example.com
Paraffin tissue sections from 50 patients with prostate adenocarcinoma were used to study nuclear and nucleolar morphometric features by image analysis. The results were compared to DNA ploidy and Gleason grade. In the examined histological samples nuclear and nucleolar areas were positively interrelated. It was also noticed that the higher the percentage of nucleolated nuclei, the bigger the nuclear and nucleolar areas. The morphometric characteristics did not differ significantly among the four grades of the examined specimens. In well-differentiated carcinomas the DNA index was lower than in the rest at a statistically significant level. Hypodiploid carcinomas were found to possess significantly bigger nuclear areas than any other DNA index group. Morphonuclear evidence of anaplasia and DNA aneuploidy may be used as diagnostic tools in prostate cancer in addition to Gleason grade.
UI - 11895872
AU - Stanford JL; Noonan EA; Iwasaki L; Kolb S; Chadwick RB; Feng Z;
TI - Ostrander EA A polymorphism in the CYP17 gene and risk of prostate cancer.
SO - Cancer Epidemiol Biomarkers Prev 2002 Mar;11(3):243-7
AD - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle 98109, USA. firstname.lastname@example.org
Steroid hormones are important in the etiology and progression of prostate cancer, and expression of genes involved in hormone production may alter susceptibility. One such gene is CYP17, which encodes the cytochrome P450c17a enzyme responsible for the biosynthesis of testosterone. A T to C transition (A2 allele) in the 5' promoter region of the gene is hypothesized to increase the rate of gene transcription, increase androgen production, and thereby increase risk of prostate cancer. To test this hypothesis, germ-line DNA samples from a large population-based study of incident prostate cancer cases (n = 590) and controls (n = 538) of similar age without the disease were genotyped. The frequency of the A2 allele was similar in cases and controls. Compared with men with the A1/A1 genotype, the adjusted odds ratio was 0.81 for the A1/A2 and 0.87 for the A2/A2 genotype. Risk estimates did not vary substantially by age or race. However, stratification by family history of prostate cancer revealed that among white men with an affected first-degree relative, homozygotes for the A2 allele had a significant elevation in risk (odds ratio = 19.2; 95% confidence interval, 2.2-157.4) compared with men who were homozygous for the A1 allele (interaction P = 0.0005). These results suggest that the CYP17 A2/A2 genotype predicts susceptibility to prostate cancer in white men with a family history of the disease. It is also possible that CYP17 interacts with other genes that influence risk of familial prostate cancer.
UI - 12096133
AU - Arnott D; Kishiyama A; Luis EA; Ludlum SG; Marsters JC Jr; Stults JT
TI - Selective detection of membrane proteins without antibodies: a mass spectrometric version of the Western blot.
SO - Mol Cell Proteomics 2002 Feb;1(2):148-56
AD - Department of Protein Chemistry, Genentech, Inc., South San Francisco, California 94080, USA. email@example.com
A method has been developed, called the mass western experiment in analogy to the Western blot, to detect the presence of specific proteins in complex mixtures without the need for antibodies. Proteins are identified with high sensitivity and selectivity, and their abundances are compared between samples. Membrane protein extracts were labeled with custom isotope-coded affinity tag reagents and digested, and the labeled peptides were analyzed by liquid chromatography-tandem mass spectrometry. Ions corresponding to anticipated tryptic peptides from the proteins of interest were continuously subjected to collision-induced dissociation in an ion trap mass spectrometer; heavy and light isotope-coded affinity tag-labeled peptides were simultaneously trapped and fragmented accomplishing identification and quantitation in a single mass spectrum. This application of ion trap selective reaction monitoring maximizes sensitivity, enabling analysis of peptides that would otherwise go undetected. The cell surface proteins prostate stem cell antigen (PSCA) and ErbB2 were detected in prostate and breast tumor cell lines in which they are expressed in known abundances spanning orders of magnitude.
UI - 12096134
AU - Li J; LeRiche T; Tremblay TL; Wang C; Bonneil E; Harrison DJ; Thibault P
TI - Application of microfluidic devices to proteomics research: identification of trace-level protein digests and affinity capture of target peptides.
SO - Mol Cell Proteomics 2002 Feb;1(2):157-68
AD - Institute for Biological Sciences, 100 Sussex Dr., Ottawa, Ontario K1A 0R6, Canada.
This report describes an integrated and modular microsystem providing rapid analyses of trace-level tryptic digests for proteomics applications. This microsystem includes an autosampler, a microfabricated device comprising a large channel (2.4 microl total volume), an array of separation channels, together with a low dead volume enabling the interface to nanoelectrospray mass spectrometry. The large channel of this microfluidic device provides a convenient platform to integrate C(18) reverse phase packing or other type of affinity media such as immobilized antibodies or immobilized metal affinity chromatography beads thus enabling affinity selection of target peptides prior to electrophoretic separation and mass spectrometry analyses on a quadrupole/time-of-flight instrument. Sequential injection, preconcentration, and separation of peptide standards and tryptic digests are achieved with a throughput of up to 12 samples/per h and a concentration detection limit of approximately 5 nM (25 fmol on chip). Replicate injections of peptide mixtures indicated that reproducibility of migration time was 1.2-1.8%, whereas relative standard deviation ranging from 9.2 to 11.8% are observed on peak heights. The application of this device for trace-level protein identification is demonstrated for two-dimensional gel spots obtained from extracts of human prostatic cancer cells (LNCap) using both peptide mass-fingerprint data base searching and on-line tandem mass spectrometry. Enrichment of target peptides prior to mass spectral analyses is achieved using c-myc-specific antibodies immobilized on protein G-Sepharose beads and facilitates the identification of antigenic peptides spiked at a level of 20 ng/ml in human plasma. Affinity selection is also demonstrated for gel-isolated protein bands where tryptic phosphopeptides are captured on immobilized metal affinity chromatography beads and subsequently separated and characterized on this microfluidic system.
UI - 12101115
AU - Xu J; Meyers DA; Sterling DA; Zheng SL; Catalona WJ; Cramer SD; Bleecker
TI - ER; Ohar J Association studies of serum prostate-specific antigen levels and the genetic polymorphisms at the androgen receptor and prostate-specific antigen genes.
SO - Cancer Epidemiol Biomarkers Prev 2002 Jul;11(7):664-9
AD - Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Testing for serum prostate-specific antigen (PSA) levels has been widely used to screen for prostate cancer. However, PSA testing has low specificity and sensitivity because PSA is not prostate cancer-specific. PSA is encoded by the APS gene, and the expression of this gene is regulated by androgens. W. Xue et al. Cancer Res., 60: 839-841, 2000 reported recently that serum PSA levels are associated with a G/A polymorphism at androgen responsive element 1 (ARE1) of APS and/or the CAG repeats in exon 1 of the androgen receptor (AR) gene. This result, if confirmed, may significantly increase the specificity and sensitivity of PSA testing by incorporating genotype-specific thresholds. In this study, we tested for the association between serum PSA levels and these single nucleotide polymorphisms (SNPs) in a large sample of 518 men. For the AR gene, we observed slightly (but not statistically significant) higher mean serum PSA levels in men with shorter CAG repeats (
UI - 12015321
AU - Masiello D; Cheng S; Bubley GJ; Lu ML; Balk SP
TI - Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor.
SO - J Biol Chem 2002 Jul 19;277(29):26321-6
AD - Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Prostate cancers (PCa) that relapse after androgen deprivation therapy invariably express high levels of androgen receptor (AR) and AR-regulated genes. Most do not respond to secondary hormonal therapies, including AR antagonists, and the mechanisms of AR activation in these clinically androgen-independent tumors are unclear. Bicalutamide, the most widely used AR antagonist, is a competitive antagonist shown previously to stabilize AR association with cytosolic heat shock protein complexes. This study found nuclear AR expression in bicalutamide-treated androgen-independent PCa and found that bicalutamide could stimulate AR nuclear translocation. Moreover, specific DNA binding by the bicalutamide-liganded AR was demonstrated in vivo using a VP16-AR fusion protein and was confirmed by chromatin immunoprecipitation showing binding to the prostate-specific antigen enhancer in LNCaP PCa cells. Nonetheless, bicalutamide could not stimulate interactions between the AR N and C termini or recruitment of steroid receptor coactivator proteins (SRC-1 or -2), although SRC transfection augmented AR activity in the presence of dihydrotestosterone and inhibitory concentrations of bicalutamide. These results demonstrate that bicalutamide stimulates the assembly of a transcriptionally inactive AR on DNA and support altered coactivator (or corepressor) expression as a mechanism of bicalutamide-resistant androgen-independent PCa.
UI - 12134144
AU - Adams JY; Johnson M; Sato M; Berger F; Gambhir SS; Carey M;
TI - Iruela-Arispe ML; Wu L Visualization of advanced human prostate cancer lesions in living mice by a targeted gene transfer vector and optical imaging.
SO - Nat Med 2002 Aug;8(8):891-7
AD - Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles California 90095, USA.
Non-invasive imaging and transcriptional targeting can improve the safety of therapeutic approaches in cancer. Here we demonstrate the ability to identify metastases in a human-prostate cancer model, employing a prostate-specific adenovirus vector (AdPSE-BC-luc) and a charge-coupled device-imaging system. AdPSE-BC-luc, which expresses firefly luciferase from an enhanced prostate-specific antigen promoter, restricted expression in the liver but produced robust signals in prostate tumors. In fact, expression was higher in advanced, androgen-independent tumors than in androgen-dependent lesions. Repetitive imaging over a three-week period after AdPSE-BC-luc injection into tumor-bearing mice revealed that the virus could locate and illuminate metastases in the lung and spine. Systemic injection of low doses of AdPSE-BC-luc illuminated lung metastasis. These results demonstrate the potential use of a non-invasive imaging modality in therapeutic and diagnostic strategies to manage prostate cancer.
UI - 12074801
AU - Grande M; Carlstrom K; Stege R; Pousette A; Faxen M
TI - Estrogens affect endothelin-1 mRNA expression in LNCaP human prostate carcinoma cells.
SO - Eur Urol 2002 May;41(5):568-72; discussion 573-4
AD - Department of Women and Child Health, Research Laboratory for Reproductive Health, Karolinska Institute, C4:U1 Karolinska Hospital, S-171 77, Stockholm, Sweden. firstname.lastname@example.org
OBJECTIVE: To study effects of estrogens on endothelin-1 (ET-1) mRNA expression in the androgen-sensitive LNCaP-FGC cell line and its androgen-resistant derivative LNCaP-r. Further, if effects of estrone sulfate (E1S) are mediated via conversion to estradiol-17beta (E2). Estrogens have been shown to down-regulate ET-1, a mediator of the osteoblastic response of bone to metastatic prostate cancer.METHODS: Cells were grown in steroid-depleted medium and incubated for 2-4 and 48 hours with 0, 1, 10, and 100 nM of either E1S or E2. mRNA levels were measured with an RT-PCR technique. Estrogen metabolism by LNCaP-FGC cells was studied by incubation with estrone (E1) and E1S at the same conditions, followed by determination of E1 and E2.RESULTS: ET-1 mRNA expression in LNCaP-FGC cells was significantly suppressed by E2 and E1S following incubation for 2-4h but after 48 h only by E2 at 1 and 10nM and in LNCaP-r cells only by E2 at 100 nM following 2-4h of incubation. ET-1 mRNA expression was significantly higher in untreated LNCaP-r than in untreated LNCaP-FGC cells. E1 was efficiently transformed into E2 by LNCaP-FGC cells but very little to E1 and no E2 was formed from E1S.CONCLUSION: ET-1 mRNA expression in LNCaP-FGC can be inhibited by E2, but also by its prehormone E1S. The lack of formation of E2 from E1S suggests a mode of action not related to classical steroid receptors. The higher level of ET-1 mRNA expression found in LNCaP-r cells may reflect the capability of a hormone refractory tumor to maintain activity on its own, independently of known regulatory mechanisms such as sex steroids.
UI - 12154022
AU - Lo SH; Lo TB
TI - Cten, a COOH-terminal tensin-like protein with prostate restricted expression, is down-regulated in prostate cancer.
SO - Cancer Res 2002 Aug 1;62(15):4217-21
AD - Center for Tissue Regeneration and Repair, Department of Orthopaedic Surgery, The University of California-Davis, Sacramento, California 95817, USA. email@example.com
Tensin is a signaling molecule that binds to actin filaments and localizes to focal adhesions. Recently, we have discovered that tensin represents a new gene family with related members that are expressed in a variety of tissues. In this study, we report the identification and characterization of a new COOH-terminal tensin-like molecule, cten. Human cten cDNA encodes a 715 amino acid sequence containing the Src homology 2 and phosphotyrosine-binding domains that are similar to the COOH termini of tensin molecules. Although cten is shorter and does not have the actin-binding domain found in other tensins, analysis of the genomic structure has suggested that cten is related to the tensin gene family. In addition, cten also localizes to focal adhesions. In contrast to other tensin members, cten expression is restricted to prostate and placenta by Northern blot analysis. Furthermore, examination of cten expression in prostate cancer/cell lines has revealed its down-regulation in tumor samples. Our studies have suggested that during evolution, cten has preserved its role in mediating signal transduction at focal adhesions through the Src homology 2 and phosphotyrosine-binding domains but has lost its function in binding to actin filaments. The evolutionary divergence has produced the first focal adhesion protein specifically expressed in the prostate and the placenta, which may be involved in preventing prostate tumor formation.
UI - 12154050
AU - Rhodes DR; Barrette TR; Rubin MA; Ghosh D; Chinnaiyan AM
TI - Meta-analysis of microarrays: interstudy validation of gene expression profiles reveals pathway dysregulation in prostate cancer.
SO - Cancer Res 2002 Aug 1;62(15):4427-33
AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
The increasing availability and maturity of DNA microarray technology has led to an explosion of cancer profiling studies. To extract maximum value from the accumulating mass of publicly available cancer gene expression data, methods are needed to evaluate, integrate, and intervalidate multiple datasets. Here we demonstrate a statistical model for performing meta-analysis of independent microarray datasets. Implementation of this model revealed that four prostate cancer gene expression datasets shared significantly similar results, independent of the method and technology used (i.e., spotted cDNA versus oligonucleotide). This interstudy cross-validation approach generated a cohort of genes that were consistently and significantly dysregulated in prostate cancer. Bioinformatic investigation of these genes revealed a synchronous network of transcriptional regulation in the polyamine and purine biosynthesis pathways. Beyond the specific implications for prostate cancer, this work establishes a much-needed model for the evaluation, cross-validation, and comparison of multiple cancer profiling studies.
UI - 12154061
AU - LaTulippe E; Satagopan J; Smith A; Scher H; Scardino P; Reuter V; Gerald
TI - WL Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease.
SO - Cancer Res 2002 Aug 1;62(15):4499-506
AD - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
The identification of genes that contribute to the biological basis for clinical heterogeneity and progression of prostate cancer is critical to accurate classification and appropriate therapy. We performed a comprehensive gene expression analysis of prostate cancer using oligonucleotide arrays with 63,175 probe sets to identify genes and expressed sequences with strong and uniform differential expression between nonrecurrent primary prostate cancers and metastatic prostate cancers. The mean expression value for >3,000 tumor-intrinsic genes differed by at least 3-fold between the two groups. This includes many novel ESTs not previously implicated in prostate cancer progression. Many differentially expressed genes participate in biological processes that may contribute to the clinical phenotype. One example was a strong correlation between high proliferation rates in metastatic cancers and overexpression of genes that participate in cell cycle regulation, DNA replication, and DNA repair. Other functional categories of differentially expressed genes included transcriptional regulation, signaling, signal transduction, cell structure, and motility. These differentially expressed genes reflect critical cellular activities that contribute to clinical heterogeneity and provide diagnostic and therapeutic targets.
UI - 12168830
AU - Noss KR; Singal R; Grimes SR
TI - Methylation state of the prostate specific membrane antigen (PSMA) CpG island in prostate cancer cell lines.
SO - Anticancer Res 2002 May-Jun;22(3):1505-11
AD - Research Service, Overton Brooks Veterans Affairs Medical Center, Shreveport, Louisiana 71101-4295, USA.
BACKGROUND: PSMA expression varies among prostate cell lines. We examined the role of CpG methylation and histone deacetylation in PSMA transcriptional repression in prostate cell lines. MATERIALS AND METHODS: The methylation status of a PSMA CpG island was investigated in LNCaP, DU145 and PC3 prostate cell lines. Cells were treated with a demethylating agent and a histone deacetylase inhibitor to determine if PSMA transcription could be activated in nonexpressing cells. A transfection assay with methylated and unmethylated PSMA promoter/enhancer-driven luciferase expression constructs was performed to examine the effect of methylation on transcription. RESULTS: The PSMA CpG island was only methylated in DU145 cells but transcription could not be activated by demethylation or histone deacetylase inhibition. Methylation repressed PSMA transcription in LNCaP cells. CONCLUSION: Although promoter methylation represses PSMA transcription in LNCaP cells, another method inhibits PSMA expression in DU145 and PC3 cells.
UI - 12174675
AU - Jovanovic BD; Huang S; Liu Y; Naguib KN; Bergan RC
TI - A simple analysis of gene expression and variability in gene arrays based on repeated observations.
SO - Am J Pharmacogenomics 2001;1(2):145-52
AD - Department of Preventive Medicine, General Clinical Research Center, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. firstname.lastname@example.org
BACKGROUND AND AIM: At the present time there is an explosion of research in the area of gene arrays, and their application for detection of genes related to disease as well as its therapeutic manipulation. However, as individual arrays are expensive, comparisons of gene expression are often not repeated. In the current study, gene array experiments were repeated multiple times in order to understand the variability associated with measurements of gene expression. By focusing upon the pharmacologically important target of prostate cancer cell detachment, the current study employed multiple repeats of gene array experiments. This was used as a model system to demonstrate the utility of the experimental approach and statistical methods used. METHODS: To identify genes involved in detachment of prostate cancer cells (a prerequisite for metastases), we analyzed gene expression changes in metastatic variant PC3-M cells undergoing spontaneous detachment in culture. The data were interpreted using an elementary statistical approach. The between-experiment and within-repeated-observations variability in expression of 3582 genes possibly related to prostate cancer was also evaluated. RESULTS: One important gene related to prostate cell detachment was identified, based on the magnitude of its change in expression, as measured by a ratio of the expression after cell detachment and expression before detachment. On average, the variation between experiments was greater by about 30 to 40% than the variation between repeated observations. CONCLUSION: These findings have implications relating to the use of gene arrays to detect variance of gene expression, and should be taken into consideration in the prospective design of array experiments.
UI - 12210487
AU - Shibata A; Garcia MI; Cheng I; Stamey TA; McNeal JE; Brooks JD;
TI - Henderson S; Yemoto CE; Peehl DM Polymorphisms in the androgen receptor and type II 5 alpha-reductase genes and prostate cancer prognosis.
SO - Prostate 2002 Sep 1;52(4):269-78
AD - Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California 94305-5405, USA. email@example.com
BACKGROUND: Cytosine-adenine-guanine repeat length of the androgen receptor gene and the A49T and V89L polymorphisms of the 5 alpha-reductase (SRD5A2) gene have been associated with prostate cancer. METHODS: We investigated the relationship of the three genetic polymorphisms to tumor grade among 211 men who had undergone radical prostatectomy. Subjects had prostate cancer <3 cm(3) with a percentage of cancer represented by Gleason grade 4 or 5 (% Gleason grade 4/5) of either > or = 20% or < or = 5%. We also examined the association between those genetic markers and prostate specific antigen (PSA) failure among 112 subjects with > or = 20% Gleason grade 4/5. RESULTS: In cross-sectional analysis, none of the polymorphisms was a significant predictor of % Gleason grade 4/5. In longitudinal analysis, the LL genotype at the V89L site was associated with statistically significant four- to sixfold increase in PSA failure risk after adjustment for clinicopathologic variables. CONCLUSIONS: We observed poorer prognosis among men with the LL genotype at codon 89 of the SRD5A2 gene. Lack of consistency between studies must be resolved before clinical utility of this marker is established. Copyright 2002 Wiley-Liss, Inc.
UI - 12210488
AU - Tsujimoto Y; Takayama H; Nonomura N; Okuyama A; Aozasa K
TI - Postatrophic hyperplasia of the prostate in Japan: histologic and immunohistochemical features and p53 gene mutation analysis.
SO - Prostate 2002 Sep 1;52(4):279-87
AD - Department of Pathology, Osaka University Medical School, Suita, Osaka, Japan.
BACKGROUND: Postatrophic hyperplasia (PAH) is one of the patterns of prostatic atrophy but has been regarded as a precursor of prostatic cancer (PCA) because of its possible increase in proliferative activity compared with simple atrophy and morphologic mimicry of PCA. METHODS: Radical prostatectomy specimens obtained from 28 patients with PCA were analyzed by histologic and immunohistochemical methods by using 34 beta E12 and Ki-67 as primary antibodies. Tissue from PAH, PCA, high-grade prostatic intraepithelial neoplasia (HGPIN), a possible precursor of PCA, and benign hyperplasia were microdissected and p53 gene mutations were examined by the polymerase chain reaction-single strand conformation polymorphism method followed by direct sequencing. RESULTS: Histologically, PAH consists of compactly arranged small acini with irregular atrophic-appearing contours, mimicking PCA. PAH lesions were detected in 7 (25%) of 28 cases with PCA: multifocal in 6 of 7 (85.7%) cases, maximum size of lesions ranged from 0.3 to 2.3 mm. Mild nuclear enlargement and small nucleoli were observed in all cases. Capsular or perineural invasion, crystalloids, and mitotic figures were not found in any case. Inflammatory changes and fibrosis near PAH were found in 100% and 71% of cases, respectively. PAH involved non-transition zone in all cases and occasionally involved transition zone. Forty-three percent of PAH lesions were in proximity (<2 mm) to PCA. None of the clinical and pathologic factors examined were correlated with the presence of PAH. Immunohistochemical analysis by using 34 beta E12 revealed intact basal cells. Proliferative activity defined by positive rate for labeling with MIB-1 antibody was intermediate between benign prostatic hyperplasia and HGPIN. The frequency of p53 mutations in PAH lesions was 5.3%, which was similar to that in HGPIN lesions (4.2%). Benign glands never showed mutations. CONCLUSION: These findings suggested that PAH might be a precursor for PCA. Copyright 2002 Wiley-Liss, Inc.
UI - 12210491
AU - Kibel AS; Faith DA; Bova GS; Isaacs WB
TI - Mutational analysis of ETV6 in prostate carcinoma.
SO - Prostate 2002 Sep 1;52(4):305-10
AD - Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. firstname.lastname@example.org
BACKGROUND: In an effort to better understand the molecular events responsible for progression of prostate carcinoma to metastatic disease, we have recently identified a homozygous deletion at 12p12-13 involving ETV6 (tel). Although mutational analysis of ETV6 has not been examined previously in prostate carcinoma, it is an attractive candidate prostate cancer tumor suppressor gene since as it previously has been implicated in malignancy. Therefore, we decided to analyze 43 prostate cell lines, xenografts, and metastatic foci for inactivating mutations. METHODS: DNA was isolated from 7 cell lines, 18 xenografts, and 18 metastatic deposits. Single-strand conformational polymorphism (SSCP) analysis of ETV6, was performed by polymerase chain reaction (PCR) amplification of each exon by using intron specific primers. PCR products were then resolved by gel electrophoresis, and aberrantly migrating PCR products were then sequenced. RESULTS: Two previously described polymorphisms and four novel sequence changes were identified. Polymorphisms at nucleotide 258 (G --> A, Thr --> Thr) and 602 (T --> C, Leu --> Pro) were identified in eight and one specimen(s), respectively. Analysis of noncancerous DNA confirmed the presence of the polymorphisms in the germ-line. Four possible mutations were identified at nucleotides 24 (T --> G, Cys --> Trp), 380 (G --> A, Arg --> Glu), 776 (G --> T, Arg --> Leu), and 876 (C --> T, Leu --> Leu). Three were in xenografts or cell lines. Because normal DNA was not available, these could represent rare polymorphisms. The sole mutation in a clinical specimen, at nucleotide 876, did not result in an amino acid change. CONCLUSION: Our data suggest that mutational inactivation ETV6 may occur in prostate carcinoma. The functional significance of these potential inactivating mutations remains to be determined. Copyright 2002 Wiley-Liss, Inc.
UI - 12210480
AU - Kawana Y; Ichikawa T; Suzuki H; Ueda T; Komiya A; Ichikawa Y; Furuya Y;
TI - Akakura K; Igarashi T; Ito H Loss of heterozygosity at 7q31.1 and 12p13-12 in advanced prostate cancer.
SO - Prostate 2002 Sep 15;53(1):60-4
AD - Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan.
BACKGROUND: Allelic losses on chromosome arms 2q, 3p, 5q, 6q, 7q, 8p, 9p, 10p, 10q, 11p, 11q, 12p, 13q, 16q, 17p, 17q, 18q, and 21q are reportedly associated with progression and/or initiation of prostate cancer. In the present study, we performed a polymerase chain reaction (PCR) analysis of polymorphic microsatellite loci on the human chromosomes 7 and 12p13-12 in prostate cancer tissue to investigate the extent of involvement of these regions, which may contain putative tumor suppressor genes. METHODS: Tissue samples were obtained at autopsy from 17 men who died of hormone-refractory prostate cancer at Chiba University, Japan, and affiliated hospitals between June of 1992 and June of 1995. DNA from normal tumor or metastatic tissue was used as the template for PCR amplification of a set of 16 polymorphic microsatellite loci on human chromosome 7 and 6 loci on the human chromosome region 12p13-12. RESULTS: The frequencies of cases with loss of heterozygosity (LOH) at 7q31.1 were 8% in primary tumor tissue and 11% in metastatic tissue. The frequencies of cases with LOH at 12p13-12 were 12% in primary tumor tissue and 25% in metastatic tumor tissue. CONCLUSIONS: In the present study, the frequencies of LOH at 7q31.1 were lower than in Western patients, suggesting that LOH in this region is not related to progression of prostate cancer in Japanese patients. The frequency of LOH at 12p13-12 was similar to that reported in Western countries, indicating that 12p13-12 may contain a tumor suppressor gene of prostate cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 12210481
AU - Margiotti K; Kim E; Pearce CL; Spera E; Novelli G; Reichardt JK
TI - Association of the G289S single nucleotide polymorphism in the HSD17B3 gene with prostate cancer in Italian men.
SO - Prostate 2002 Sep 15;53(1):65-8
AD - Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, California 90089-9075, USA.
BACKGROUND: Prostate cancer is a significant public health problem in this country. Substantial data support a plausible role for androgens in the etiology of this disease. The human HSD17B3 gene encodes the testicular (or type III) 17 beta-hydroxysteroid dehydrogenase enzyme, which catalyzes testosterone biosynthesis in men. METHODS: We have investigated the G289S (glycine at codon 289 replaced by serine) polymorphism at the HSD17B3 locus as a candidate single nucleotide polymorphism (SNP) for prostate cancer risk in constitutional DNA from 103 Italian prostate cancer patients and 109 Italian disease-free centenarians to assess the role of this SNP in susceptibility to prostate cancer. RESULTS: The G289S polymorphism confers a significant increase in risk for prostate cancer (odds ratio = 2.5; 95% confidence interval, 1.03-6.07) in our study population. CONCLUSION: Our data are consistent with a plausible role of the G289S SNP in prostate cancer susceptibility. Therefore, the HSD17B3 gene may be a plausible candidate gene for prostate cancer risk. Copyright 2002 Wiley-Liss, Inc.
UI - 12210484
AU - Medeiros R; Morais A; Vasconcelos A; Costa S; Pinto D; Oliveira J;
TI - Carvalho R; Lopes C Linkage between polymorphisms in the prostate specific antigen ARE1 gene region, prostate cancer risk, and circulating tumor cells.
SO - Prostate 2002 Sep 15;53(1):88-94
AD - Molecular Oncology Unit, Instituto Portugues de Oncologia, Porto, Portugal. email@example.com
BACKGROUND: The prostate specific antigen (PSA) gene has a polymorphic androgen response element (ARE) sequence with two alleles, A and G. PSA A-allele carriers have higher serum PSA levels in healthy men (HM). METHODS: We analysed DNA samples from 278 (556 alleles) unrelated individuals, 127 HM and 151 prostate cancer (PC) patients, for PSA ARE1 genotypes. RESULTS: The analysis of the frequencies from the 556 alleles indicates a significant overrepresentation of A-allele in the PC group under the age of 67 compared with the HM group (63.3% vs. 48.8%; P = 0.009). We found that men carrying two A-alleles have increased risk for PC onset under the age of 67 (odds ratio [OR] = 2.92; 95% confidence interval [CI], 1.10-7.86; P = 0.013). Multivariate logistic regression analysis confirmed this association (OR = 1.82; 95% CI, 1.03-3.22; P = 0.037). Furthermore, the homozygosity for the A-allele was associated with higher serum PSA levels (P = 0.027) and with the presence of circulating tumor cells in the blood of PC patients (P = 0.018). CONCLUSION: Our results indicate that polymorphism in the PSA gene promoter may be an important biomarker for prostate cancer risk, especially for an earlier onset of PC. Copyright 2002 Wiley-Liss, Inc.
UI - 11444857
AU - Yeh CC; Lee C; Dahiya R
TI - DNA mismatch repair enzyme activity and gene expression in prostate cancer.
SO - Biochem Biophys Res Commun 2001 Jul 13;285(2):409-13
AD - Department of Urology, Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA.
Microsatellite instability (MSI) of short repetitive sequences in human chromosomal DNA can result from defective DNA mismatch repair function in tumor cells. We hypothesize that DNA mismatch repair (MMR) activity is down-regulated during prostatic carcinogenesis. To test this hypothesis, MMR activities and mismatch repair-related genes were analyzed in five different prostate cancer cell lines. Our results demonstrate that MMR activities were decreased as compared to MMR proficient HeLa cells. Interestingly, LNCaP, PC-3 and DU145 had much lower MMR activities as compared to DUPro and TSUPr1. The MMR-related genes (hMLH1, hPMS1, hPMS2, hMSH2, hMSH3, hMSH6) showed mRNA transcripts in all prostate cancer cell lines. However, Western blotting showed decreased or absent hMLH1 protein expression in PC-3, DU145, DUPro and TSUPr1 cells. Similarly, the hMSH2 protein expression was low or absent in DU145 and LNCaP cells. This is the first report that demonstrates decreased MMR activities is associated with low expression of hMLH1, hMSH2 and other MMR-related proteins in prostate cancer. Copyright 2001 Academic Press.
UI - 11704864
AU - Catz SD; Johnson JL
TI - Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer.
SO - Oncogene 2001 Nov 1;20(50):7342-51
AD - Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, CA 92037, USA.
This work presents direct evidence that the bcl-2 gene is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B) and directly links the TNF-alpha/NF-kappa B signaling pathway with Bcl-2 expression and its pro-survival response in human prostate carcinoma cells. DNase I footprinting, gel retardation and supershift analysis identified a NF-kappa B site in the bcl-2 p2 promoter. In the context of a minimal promoter, this bcl-2 p2 site 1 increased transcription 10-fold in the presence of the p50/p65 expression vectors, comparable to the increment observed with the consensus NF-kappa B site, while for the full p2 promoter region transcriptional activity was increased sixfold by over-expression of NF-kappa B, an effect eliminated by mutating the bcl-2 p2 site 1. The expression of Bcl-2 has been linked to the hormone-resistant phenotype of advanced prostate cancer. Here we show that an increase in the level of expression of Bcl-2 in the human prostate carcinoma cell line LNCaP observed in response to hormone withdrawal is further augmented by TNF-alpha treatment, and this effect is abated by inhibitors of NF-kappa B. Concomitantly, bcl-2 p2 promoter studies in LNCaP cells show a 40-fold increase in promoter activity after stimulation with TNF-alpha in the absence of hormone.
UI - 12187189
AU - Bratt O
TI - Hereditary prostate cancer: clinical aspects.
SO - J Urol 2002 Sep;168(3):906-13
AD - Unit for Urology, Helsingborg Hospital, Sweden.
PURPOSE: We review the current epidemiological and genetic knowledge regarding hereditary prostate cancer, and outline its clinical implications. MATERIALS AND METHODS: Published articles on hereditary prostate cancer were identified using the MEDLINE data base. RESULTS: A risk of prostate cancer, particularly early onset disease, is strongly affected by family history (number of relatives with prostate cancer and their age at diagnosis). A family history of prostate cancer increases the positive predictive value of prostate specific antigen testing and, hence, heredity should always be assessed when deciding whether to perform biopsies in a man with a prostate specific antigen level of 3 to 10 ng./ml. Epidemiological studies indicate that dominantly inherited susceptibility genes with high penetrance cause 5% to 10% of all prostate cancer cases, and as much as 30% to 40% of early onset disease. More than a half dozen chromosome loci that may comprise such genes have of major importance had been cloned. Most likely, environmental factors and comparatively common variants of several other genes affect prostate cancer risk in families with or without multiple cases of the disease. On average, hereditary prostate cancer is diagnosed 6 to 7 years earlier than sporadic prostate cancer, but does not otherwise differ clinically from the sporadic form. As a consequence of the earlier onset, a greater proportion of men with hereditary prostate cancer die of the disease than those with nonhereditary prostate cancer. At present, the only clinically applicable measure to reduce prostate cancer mortality in families with hereditary disease is screening, with the aim of diagnosing the disease when it is still in a curable stage. CONCLUSIONS: Hereditary susceptibility is now considered the strongest risk factor for prostate cancer and has profound clinical importance. The genetic mechanism behind such susceptibility has turned out to be more complex than initially thought, and will probably not be completely understood for many years to come.
UI - 12202660
AU - Bennett CL; Price DK; Kim S; Liu D; Jovanovic BD; Nathan D; Johnson ME;
TI - Montgomery JS; Cude K; Brockbank JC; Sartor O; Figg WD Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status.
SO - J Clin Oncol 2002 Sep 1;20(17):3599-604
AD - Mid-West Center for Health Services Research and Development, Department of Veterans Affairs Medical Center, Chicago, IL 60611, USA. firstname.lastname@example.org
PURPOSE: To evaluate (1) whether there were racial differences in the androgen receptor gene CAG repeat length and in clinical or laboratory attributes of prostate cancer at the time of diagnosis; (2) whether there were differences in race, Gleason score, prostate-specific antigen (PSA) level, and stage at diagnosis by androgen receptor gene CAG repeat length; and (3) whether sociodemographic, clinical, and laboratory based factors might be associated with advanced-stage prostate cancer. To our knowledge, our study is the first to report on CAG repeat lengths in a cohort of prostate cancer patients, which includes large numbers of African-American men. METHODS: CAG repeat lengths on the androgen receptor gene were evaluated for 151 African-American and 168 white veterans with prostate cancer. The chi(2) test, t test, and logistic regression analyses were used to evaluate the associations between CAG repeat lengths and race, stage, histologic grade, and PSA levels at diagnosis. RESULTS: The mean age of the cohort at the time of diagnosis was 68.7 years. At presentation, 42.0% had stage D prostate cancer, 26.5% had Gleason scores of 8 to 10, and 53.0% had PSA levels >/= 10 ng/dL. Mean androgen receptor gene CAG repeat length for white veterans was 21.9 (SD, 3.5) versus 19.8 (SD, 3.2) for African-American veterans (P =.001). Men with shorter CAG repeats were more likely to have stage D prostate cancer (P =.09) but were not more likely to have a higher PSA concentration or Gleason score. CONCLUSION: In this cohort of men with prostate cancer, short CAG repeat length on the androgen receptor gene was associated with African-American race and possibly with higher stage but not with other clinical or pathologic findings.
UI - 12165860
AU - Zhang Y; Fondell JD; Wang Q; Xia X; Cheng A; Lu ML; Hamburger AW
TI - Repression of androgen receptor mediated transcription by the ErbB-3 binding protein, Ebp1.
SO - Oncogene 2002 Aug 15;21(36):5609-18
AD - Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, MD 21201, USA.
Members of the ErbB family of receptors have been implicated in regulation of androgen receptor (AR) activity. Ebp1, an ErbB-3 binding protein recently cloned in our laboratory, possesses an LXXLL motif important in mediating interactions with nuclear hormone receptors. Therefore, we sought to determine if Ebp1 could bind AR and influence AR transcriptional activation potential. We demonstrate in this study that Ebp1 bound to AR in vitro and in vivo, and that this binding was increased by androgen treatment. The C terminal 79 amino acids of Ebp1 were sufficient to bind AR. The N terminal domain of AR was responsible for binding Ebp1. Ligand-mediated transcriptional activation of both artificial and natural AR regulated promoters was inhibited by ectopic expression of ebp1 in transient transfection systems. Ebp1 deletion mutants that either lacked the C terminal AR binding region or had a mutated LXXLL motif failed to inhibit AR activated transcription. PSA expression from its endogenous promoter was also decreased in LNCaP prostate cancer cells overexpressing Ebp1. The growth of AR positive LNCaP cells was inhibited by ectopic expression of ebp1, but mutants that failed to repress transcription did not inhibit cell growth. These studies suggest that Ebp1 may play a role in the function of the AR and provide a link between ErbB receptors and the AR.