National Cancer Institute®
Last Modified: August 1, 2002
UI - 12107087
AU - Shih SC; Robinson GS; Perruzzi CA; Calvo A; Desai K; Green JE; Ali IU;
TI - Smith LE; Senger DR Molecular profiling of angiogenesis markers.
SO - Am J Pathol 2002 Jul;161(1):35-41
AD - Department of Ophthalmology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure copy numbers of specific mRNAs using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and identify a profile of gene expression closely associated with angiogenesis. We measured a panel of nine potential angiogenesis markers from a mouse transgenic model of prostate adenocarcinoma (TRAMP) and a mouse skin model of vascular endothelial growth factor (VEGF)-driven angiogenesis. In both models, expression of VEGF correlated with expression of mRNAs encoding other angiogenic cytokines (angiopoietin-1 and angiopoietin-2), endothelial cell receptor tyrosine kinases (Flt-1, KDR, Tie-1), and endothelial cell adhesion molecules (VE-cadherin, PECAM-1). Relative to control, in dermis highly stimulated by VEGF, the Ang-2 mRNA transcript numbers increased 35-fold, PECAM-1 and VE-cadherin increased 10-fold, Tie-1 increased 8-fold, KDR and Flt-1 each increased 4-fold, and Ang-1 increased 2-fold. All transcript numbers were correspondingly reduced in skin with less VEGF expression, indicating a relationship of each of these seven markers with VEGF. Thus, this study identifies a highly efficient method for precise quantification of a panel of seven specific mRNAs that correlate with VEGF expression and VEGF-induced neovascularization, and it provides evidence that real-time quantitative RT-PCR offers a highly sensitive strategy for monitoring angiogenesis.
UI - 11855735
AU - Ye Q; Cinar B; Edlund M; Chung LW; Zhau HE
TI - Inhibition of growth and cell cycle arrest of ARCaP human prostate cancer cells by ectopic expression of ER-alpha.
SO - Mol Cell Biochem 2001 Dec;228(1-2):105-10
AD - Department of Urology, University of Virginia School of Medicine, Charlottesville 22908, USA. QY3X@Virginia.edu
The estrogen receptor-alpha (ER-alpha) is a ligand-dependent transcription factor that regulates the growth, differentiation, and development of hormone-responsive target organs. While ER-alpha has been reported to play critical role in the pathogenesis and prognosis of breast and prostate cancers, its possible functional role in regulating prostate cancer cell growth in a ligand-dependent or -independent manner is poorly understood. We addressed this question by stably transfecting wild type (wt) ER-alpha cDNA into an invasive estrogen receptor-negative human prostate cancer cell line ARCaP. We isolated several clonal lines of transfected cells expressing varying levels of ER-alpha. The ectopic expression of wt ER-a markedly inhibited the growth of ARCaP cells in vitro in an ER-a dose-dependent but ligand-independent manner. Flow cytometric analysis of the wt ER-alpha-transfected ARCaP cells revealed that wt ER-alpha expression arrested cell growth in G1 phase. Our results suggest that ER-alpha may regulate prostate cell growth and participate in the pathogenesis of prostate cancer. ER-alpha may be delivered and expressed ectopically to target prostate cancer progression.
UI - 12115574
AU - Burger MJ; Tebay MA; Keith PA; Samaratunga HM; Clements J; Lavin MF;
TI - Gardiner RA Expression analysis of delta-catenin and prostate-specific membrane antigen: their potential as diagnostic markers for prostate cancer.
SO - Int J Cancer 2002 Jul 10;100(2):228-37
AD - Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane, Australia.
The current approach to prostate cancer diagnosis has major limitations including the inability of prostate-specific antigen (PSA) assays to accurately differentiate between prostate cancer and benign prostate hyperplasia (BPH) and the imprecision of transrectal ultrasound (TRUS) biopsy sampling. We have employed cDNA microarray screening to compare gene expression patterns in BPH and tumour samples to identify expression markers that may be useful in discriminating between these conditions. Screening of 3 individual cDNA arrays identified 8 genes with expression 3-fold greater in 6 tumour tissues than in 1 nontumour sample and 1 BPH sample. Real-time PCR was used to confirm the overexpression of these 8 genes and 12 genes selected from the literature against a panel of 17 tumours and 11 BPH samples. Two genes, delta-catenin (delta-catenin; CTNND2) and prostate-specific membrane antigen (PSMA; FOLH1), were significantly overexpressed in prostate cancer compared to BPH. Prostate epithelial cells stained positively for delta-catenin and PSMA in our prostate cancer tissues, whereas the majority of our BPH tissues were negative for both markers. Thus we have identified delta-catenin (not previously associated with prostatic adenocarcinoma) and confirmed the potential of PSMA as potential candidates for the diagnosis and management of prostate cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 12118091
AU - Kanno T; Endo H; Takeuchi K; Morishita Y; Fukayama M; Mori S
TI - High expression of methionine aminopeptidase type 2 in germinal center B cells and their neoplastic counterparts.
SO - Lab Invest 2002 Jul;82(7):893-901
AD - Division of Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. firstname.lastname@example.org
Methionine aminopeptidase type 2 (MetAP2) is a bifunctional protein that plays critical roles in the regulation of protein synthesis and post-translational processing by (a) protecting the alpha subunit of eukaryotic initiation factor 2 from inhibitory phosphorylation by eukaryotic initiation factor 2 kinases and (b) removing the amino-terminal methionine residue from nascent protein. MetAP2 is also known as the molecular target of the angiogenesis inhibitor TNP-470. In addition, it has been recently suggested that MetAP2 has an antiapoptotic function in mesothelioma. To know the pattern of expression of MetAP2 in normal and neoplastic tissues, we raised two specific rabbit polyclonal Abs and examined the pattern of MetAP2 expression in various normal and pathologic specimens. Unexpectedly, we found a very high and selective expression of MetAP2 in germinal center B cells. In the germinal center, dark zone B cells tended to express more MetAP2 than light zone B cells. When 200 malignant lymphomas of various subtypes were studied, a high level of MetAP2 expression, equivalent to that observed in germinal center B cells, was noted exclusively on B-cell lymphoma subtypes that are currently regarded as the neoplastic counterparts of germinal center B cells. The expression of MetAP2 in diffuse large B-cell lymphomas correlated well with that of BCL6 (p < 0.05) but not with that of either CD10 or BCL2. These data suggest that MetAP2 has specific function(s) in germinal center B cells and that the function is shared by neoplastic counterparts of germinal center B cells.
UI - 11948106
AU - Corey E; Quinn JE; Emond MJ; Buhler KR; Brown LG; Vessella RL
TI - Inhibition of androgen-independent growth of prostate cancer xenografts by 17beta-estradiol.
SO - Clin Cancer Res 2002 Apr;8(4):1003-7
AD - Department of Urology, University of Washington, Seattle, Washington 98195, USA. email@example.com
PURPOSE: Estrogen treatment has long been known to be of benefit in prostate cancer (CaP), but its mechanism was thought to involve merely a reduction in androgen levels. However, new evidence indicates that estrogen may exert effects on CaP cells in the absence of androgens. EXPERIMENTAL DESIGN: Implantation of CaP xenografts (LuCaP 35, LuCaP 49, LuCaP 58, LuCaP 73, PC-3, and LNCaP) into intact and ovariectomized female mice was done to characterize growth and take rates in the absence of androgens. Ovariectomized female mice were supplemented with 17beta-estradiol, and LuCaP 35 CaP xenograft take and growth rates were determined. Reverse transcription-PCR was used to evaluate the presence of the estrogen receptor messages in CaP xenografts. RESULTS: We have observed significant inhibition of CaP growth in intact versus ovariectomized female animals in five of six CaP xenograft lines. 17beta-Estradiol supplements given to ovariectomized female mice led to inhibition of tumor establishment and diminished growth of LuCaP 35 similar to that observed in intact female mice. Using reverse transcription-PCR, we have shown that these xenografts express the estrogen receptor beta message. CONCLUSIONS: We have determined that 17beta-estradiol supplementation causes inhibition of CaP growth in an animal model by mechanisms that are independent of androgen action. This gives rise to the possibility that estrogen therapy may be of potential use with hormone-refractory cancers. The xenograft models we describe herein may be useful as well in elucidating the pathways mediating the androgen-independent effects of estrogen on CaP.
UI - 11948125
AU - Reubi JC; Wenger S; Schmuckli-Maurer J; Schaer JC; Gugger M
TI - Bombesin receptor subtypes in human cancers: detection with the universal radioligand (125)I-[D-TYR(6), beta-ALA(11), PHE(13), NLE(14)] bombesin(6-14).
SO - Clin Cancer Res 2002 Apr;8(4):1139-46
AD - Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland. firstname.lastname@example.org
PURPOSE: Bombesin and bombesin receptors have been shown to play a role in cancer. Whereas the gastrin-releasing peptide (GRP) receptor is a bombesin receptor subtype frequently expressed by tumors, the other three subtypes, the neuromedin B (NMB), BB3, and BB4 receptors, have been poorly investigated in human tissues. EXPERIMENTAL DESIGN: We investigated 161 human tumors for their bombesin receptor subtype expression using in vitro receptor autoradiography with the universal bombesin radioligand (125)I-[D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]bombesin(6-14) in displacement experiments with unlabeled GRP, bombesin, NMB, and [D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)]bombesin(6-14). The distinct rank order of potencies of these analogues for each receptor subtype allows us to identify the predominant subtype expressed by each tumor. RESULTS: Twelve of 12 prostate cancers, 41 of 57 breast cancers, and 5 of 5 gastrinomas expressed predominantly GRP receptors; 11 of 24 intestinal, 1 of 26 bronchial, and 1 of 1 thymic carcinoids had preferentially NMB receptors; 9 of 26 bronchial carcinoids, 1 large cell neuroendocrine lung carcinoma, and 4 of 9 small cell lung carcinomas had preferentially BB3 receptors, whereas 3 of 9 small cell lung carcinomas had GRP receptors. Renal cell carcinomas had GRP receptors in 6 of 16 cases and BB3 receptors in 4 of 16 cases. Finally, 2 of 10 Ewing sarcomas had BB3 receptors. In situ hybridization detected BB3 receptor mRNA in neuroendocrine tumors expressing the BB3 protein. CONCLUSIONS: This is the first study detecting the proteins of BB3, NMB, and GRP receptors in a group of human tumors using differential binding techniques. Particularly relevant is the BB3 expression in lung carcinoids and other neuroendocrine lung tumors, whereas gastrointestinal carcinoids preferably express NMB receptors. These tumors may be targets for diagnostic and radiotherapeutic applications of subtype-selective bombesin analogues.
UI - 12006585
AU - Robles LD; Frost AR; Davila M; Hutson AD; Grizzle WE; Chakrabarti R
TI - Down-regulation of Cdc6, a cell cycle regulatory gene, in prostate cancer.
SO - J Biol Chem 2002 Jul 12;277(28):25431-8
AD - Department of Molecular Biology and Microbiology, University of Central Florida, Orlando 32826-2362, USA.
CDC6 plays a critical role in regulation of the onset of DNA replication in eukaryotic cells. We have found that Cdc6 expression is down-regulated in prostate cancer as detected by semiquantitative reverse transcriptase-PCR of prostate cell lines and laser-captured microdissected prostate tissues. This result was substantiated by immunohistochemical analysis of paraffin-embedded tissue sections and immunoblot analysis of benign (BPH-1) and adenocarcinomatous prostatic cells. Furthermore, a 100-fold reduction in the transcription efficiency of the Cdc6 promoter-luciferase construct was noted in the metastatic PC3 cells compared with that in BPH-1 cells. Concentration of the E2F and Oct1 transcription factors that have putative binding sites in the Cdc6 promoter was substantially low in PC3 cells compared with BPH cells. Mutagenesis of the two E2F binding sites on the Cdc6 promoter resulted in increased promoter activity in PC3 cells owing to elimination of the negative regulation by pRb.E2F complex but not to the level of that obtained in BPH cells. We conclude that an altered interaction of transcription factors may be responsible for the down-regulation of Cdc6 transcription in PC3 cells. Our study suggests a potential use of the lack of CDC6 expression as an index of prostate cancer development.
UI - 12086875
AU - Abeele FV; Skryma R; Shuba Y; Van Coppenolle F; Slomianny C; Roudbaraki
TI - M; Mauroy B; Wuytack F; Prevarskaya N Bcl-2-dependent modulation of Ca(2+) homeostasis and store-operated channels in prostate cancer cells.
SO - Cancer Cell 2002 Mar;1(2):169-79
AD - Laboratoire de Physiologie Cellulaire, INSERM EPI-9938, Universite des Sciences et Technologies de Lille, Batiment SN3, 59655 Villeneuve d'Ascq Cedex, France.
Antiapoptotic oncoprotein Bcl-2 has extramitochondrial actions due to its localization on the endoplasmic reticulum (ER); however, the specific mechanisms of such actions remain unclear. Here we show that Bcl-2 overexpression in LNCaP prostate cancer epithelial cells results in downregulation of store-operated Ca(2+) current by decreasing the number of functional channels and inhibiting ER Ca(2+) uptake through a reduction in the expression of calreticulin and SERCA2b, two key proteins controlling ER Ca(2+) content. Furthermore, we demonstrate that Ca(2+) store depletion by itself is not sufficient to induce apoptosis in Bcl-2 overexpressing cells, and that sustained Ca(2+) entry via activated store-operated channels (SOCs) is required as well. Our data therefore suggest the pivotal role of SOCs in apoptosis and cancer progression.
UI - 12086878
AU - Singh D; Febbo PG; Ross K; Jackson DG; Manola J; Ladd C; Tamayo P;
TI - Renshaw AA; D'Amico AV; Richie JP; Lander ES; Loda M; Kantoff PW; Golub TR; Sellers WR Gene expression correlates of clinical prostate cancer behavior.
SO - Cancer Cell 2002 Mar;1(2):203-9
AD - Department of Adult Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Prostate tumors are among the most heterogeneous of cancers, both histologically and clinically. Microarray expression analysis was used to determine whether global biological differences underlie common pathological features of prostate cancer and to identify genes that might anticipate the clinical behavior of this disease. While no expression correlates of age, serum prostate specific antigen (PSA), and measures of local invasion were found, a set of genes was identified that strongly correlated with the state of tumor differentiation as measured by Gleason score. Moreover, a model using gene expression data alone accurately predicted patient outcome following prostatectomy. These results support the notion that the clinical behavior of prostate cancer is linked to underlying gene expression differences that are detectable at the time of diagnosis.
UI - 12112525
AU - Tsuchiya N; Slezak JM; Lieber MM; Bergstralh EJ; Jenkins RB
TI - Clinical significance of alterations of chromosome 8 detected by fluorescence in situ hybridization analysis in pathologic organ-confined prostate cancer.
SO - Genes Chromosomes Cancer 2002 Aug;34(4):363-71
AD - Department of Urology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Loss of 8p22 and gain of 8q24 are known to be common chromosomal alterations in prostate cancer. We have previously demonstrated that concurrent 8q24 overrepresentation and 8p22 loss were associated with a poor prognosis in patients with high-grade, locally advanced prostate cancer. We evaluated the alteration of 8p22 and 8q24 in a large cohort of pathologic organ-confined prostate cancer using fluorescence in situ hybridization (FISH) analysis. All 195 patients with Gleason scores > 5, pathologic stage T(2)N(0)M(0) (pT(2)N(0)M(0)) prostate cancer, who underwent a radical prostatectomy at the Mayo Clinic between 1987 and 1991, and for whom blocks were available, were selected for this study. The median follow-up period was 9.5 years, and endpoints of this study were biochemical and clinical disease progression. The latter includes local as well as systemic disease progression. FISH analysis using paraffin-embedded tissues was performed for 8p22 (LPL), centromere 8 (8cen), and 8q24 (MYC) and was successful for 156 tumors (80.0%). Of these tumors, 104 (66.6%) had one or more numeric alterations of the 3 loci evaluated. An increased copy number of 8q24 was observed in 66 (42.3%) tumors, of which 20 (12.8%) had an additional increase (AI) of 8q24, and 46 (29.5%) had a gain of 8q24 with an equivalent gain of 8cen. Losses and gains of 8p22 were detected in 81 (51.9%) and 20 (12.8%) tumors, respectively. An AI of 8q24 was significantly associated with the tumor Gleason score (P = 0.042). Univariate analysis indicated that loss of 8p22 was a significant predictor of biochemical and clinical disease progression (P = 0.025 and P = 0.011, respectively). Furthermore, the group with loss of 8p22 concurrent with an AI of 8q24 (Loss 8p22-any 8cen-AI 8q24) had an increased rate of biochemical disease progression (P = 0.052). Multivariate analysis demonstrated that neither individual nor the Loss-any-AI combination of alterations was a significant independent predictor of disease progression when adjusting for Gleason score, preoperative PSA levels, and DNA ploidy. These data suggest that loss of 8p22 is associated with a poor prognosis, specifically when it is accompanied by AI of 8q24 in pT(2)N(0)M(0) prostate cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 12107441
AU - Kittles RA; Chen W; Panguluri RK; Ahaghotu C; Jackson A; Adebamowo CA;
TI - Griffin R; Williams T; Ukoli F; Adams-Campbell L; Kwagyan J; Isaacs W; Freeman V; Dunston GM CYP3A4-V and prostate cancer in African Americans: causal or confounding association because of population stratification?
SO - Hum Genet 2002 Jun;110(6):553-60
AD - National Human Genome Center, Howard University, Washington, DC 20060, USA. email@example.com
CYP3A4-V, an A to G promoter variant associated with prostate cancer in African Americans, exhibits large differences in allele frequency between populations. Given that the African American population is genetically heterogeneous because of its African ancestry and subsequent admixture with European Americans, case-control studies with African Americans are highly susceptible to spurious associations. To test for association with prostate cancer, we genotyped CYP3A4-V in 1376 (2 N) chromosomes from prostate cancer patients and age- and ethnicity-matched controls representing African Americans, Nigerians, and European Americans. To detect population stratification among the African American samples, 10 unlinked genetic markers were genotyped. To correct for the stratification, the uncorrected association statistic was divided by the average of association statistics across the 10 unlinked markers. Sharp differences in CYP3A4-V frequencies were observed between Nigerian and European American controls (0.87 and 0.10, respectively; P<0.0001). African Americans were intermediate (0.66). An association uncorrected for stratification was observed between CYP3A4-V and prostate cancer in African Americans (P=0.007). A nominal association was also observed among European Americans (P=0.02) but not Nigerians. In addition, the unlinked genetic marker test provided strong evidence of population stratification among African Americans. Because of the high level of stratification, the corrected P-value was not significant (P=0.25). Follow-up studies on a larger dataset will be needed to confirm whether the association is indeed spurious; however, these results reveal the potential for confounding of association studies by using African Americans and the need for study designs that take into account substructure caused by differences in ancestral proportions between cases and controls.
UI - 12124319
AU - Bonham M; Arnold H; Montgomery B; Nelson PS
TI - Molecular effects of the herbal compound PC-SPES: identification of activity pathways in prostate carcinoma.
SO - Cancer Res 2002 Jul 15;62(14):3920-4
AD - Divisions of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Clinical trials of the herbal preparation PC-SPES have demonstrated substantial responses in patients with advanced prostate cancer. Biochemical assays and clinical observations suggest that the effects of PC-SPES are mediated at least in part through estrogenic activity, although the mechanism(s) remains largely undefined. In this study, we used cDNA microarray analysis to identify gene expression changes in LNCaP prostate carcinoma cells exposed to PC-SPES and estrogenic agents including diethylstilbestrol. PC-SPES altered the expression of 156 genes after 24 h of exposure. Of particular interest, transcripts encoding cell cycle-regulatory proteins, alpha- and beta-tubulins, and the androgen receptor were down-regulated by PC-SPES. A comparison of gene expression profiles resulting from these treatments indicates that PC-SPES exhibits activities distinct from those attributable to diethylstilbestrol and suggests that alterations in specific genes involved in modulating the cell cycle, cell structure, and androgen response may be responsible for PC-SPES-mediated cytotoxicity.
UI - 11956079
AU - Xu J; Zheng SL; Turner A; Isaacs SD; Wiley KE; Hawkins GA; Chang BL;
TI - Bleecker ER; Walsh PC; Meyers DA; Isaacs WB Associations between hOGG1 sequence variants and prostate cancer susceptibility.
SO - Cancer Res 2002 Apr 15;62(8):2253-7
AD - Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
8-Hydroxyguanine is a mutagenic base lesion produced by reactive oxygen species. The hOGG1 gene encodes a DNA glycosylase/AP lyase that can suppress the mutagenic effects of 8-hydroxyguanine by catalyzing its removal from oxidized DNA. A population-based (245 cases and 222 controls) and family-based (159 hereditary prostate cancer families) association study was performed to test the hypothesis that sequence variants of hOGG1 increase susceptibility to prostate cancer. We found that the genotype frequency of two sequence variants (11657A/G and Ser326Cys) was significantly different between cases and controls. The association with 11657A/G is confirmed and strengthened by our family-based association study. These results suggest that sequence variants in this gene are associated with prostate cancer risk, presumably through defective DNA repair function of hOGG1.
UI - 12048968
AU - Weinrich SP; Faison-Smith L; Hudson-Priest J; Royal C; Powell I
TI - Stability of self-reported family history of prostate cancer among African American men.
SO - J Nurs Meas 2002 Spring-Summer;10(1):39-46
AD - School of Nursing, University of Louisville, Kentucky 40292, USA. firstname.lastname@example.org
The genome-wide search for the prostate cancer gene holds the promise of the availability of prostate cancer susceptibility testing in the near future. When this occurs, self-reported history of prostate cancer will be critical in determining who is eligible for cancer susceptibility testing. Little attention has been given to the reliability of self-reported family history of prostate cancer, particularly in African American men. This correlational study measured the stability of self-reported family history of prostate cancer over a one-year time period (between 1997 and 1998) with 96 African American men from a southern state. The men were asked on two separate occasions, 1 year apart, "Have any of your men blood relatives ever had prostate cancer?" The question had a prior test-retest reliability of 0.85 over a 2-week period. Forty-eight percent of the men changed their answers on the second administration. Men most likely to change their answers were low-income men and men who did not participate in a free prostate cancer screening. This research highlights the need for public genetic education and the recognition by health professionals that self-reported family history of cancer is a variable that changes as families have increased awareness and communication concerning family history of cancer.
UI - 12111696
AU - Rice L; Samedi VG; Medrano TA; Sweeney CA; Baker HV; Stenstrom A; Furman
TI - J; Shiverick KT Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts.
SO - Prostate 2002 Aug 1;52(3):201-12
AD - Department of Surgery, Division of Urology, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.
BACKGROUND: Isoflavones inhibit the growth of some types of tumor cells, including prostate adenocarcinoma. This study used LNCaP cells and xenografts to investigate the mechanisms of the antiproliferative effects of biochanin A, a major isoflavone present in red clover but not soy-derived products. METHODS: LNCaP cells were exposed to varying doses of biochanin A to evaluate viability, DNA synthesis, and DNA fragmentation (TUNEL) analysis. Regulation of gene expression was determined by using Western immunoblotting and cDNA microarrays. Anti-tumorigenic effects were evaluated by using athymic mice with LNCaP flank tumors. RESULTS: Biochanin A induced a dose-dependent inhibition of proliferation and [(3)H]thymidine incorporation that correlated with increased DNA fragmentation, indicative of apoptosis. Western blot analyses of cell cycle regulatory proteins revealed that biochanin A significantly decreased expression of cyclin B and p21, whereas flow cytometry showed that cells were accumulating in the G(0)/G(1) phase. cDNA microarray analyses identified 29 down-regulated genes with six reduced below assay detection limits. Eleven genes were up-regulated, including 9 that were undetectable in controls. In mice with LNCaP xenografts, biochanin A significantly reduced tumor size and incidence. CONCLUSION: These results indicate that biochanin A inhibits prostate cancer cell growth through induction of cell cycle arrest and apoptosis. Biochanin A-regulated genes suggest multiple pathways of action. Biochanin A inhibits the incidence and growth of LNCaP xenograft tumors in athymic mice. Copyright 2002 Wiley-Liss, Inc.
UI - 12111697
AU - Hsing AW; Reichardt JK; Stanczyk FZ
TI - Hormones and prostate cancer: current perspectives and future directions.
SO - Prostate 2002 Aug 1;52(3):213-35
AD - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20852-7234, USA. email@example.com
Prostate cancer is the most commonly diagnosed non-skin cancer in men in most western countries. Despite the high morbidity and mortality from prostate cancer, its etiology remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data on humans are inconclusive. To provide insights and directions for future epidemiologic research on hormones and prostate cancer, this review focuses on current perspectives of serum-based studies and polymorphisms in relevant hormone-related genes. We highlight the importance of methodologic studies and investigations of hormone levels in the prostatic tissue to help clarify the often-contradictory data on serologic studies. We recommend careful analysis and cautious interpretation of studies of genetic markers, including repeats and single nucleotide polymorphisms (SNPs), as false positive and negative results may arise in many current and future studies with limited statistical power and non-representative samples from the population. The review also highlights the reasons to perform functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations.The time is ripe for large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.
UI - 12122114
AU - Nanni S; Narducci M; Della Pietra L; Moretti F; Grasselli A; De Carli P;
TI - Sacchi A; Pontecorvi A; Farsetti A Signaling through estrogen receptors modulates telomerase activity in human prostate cancer.
SO - J Clin Invest 2002 Jul;110(2):219-27
AD - Molecular Oncogenesis Laboratory and Urology Division, Regina Elena Cancer Institute, Experimental Research Center, Rome, Italy.
Sex steroid hormone receptors play a central role in all stages of prostate cancer. Here, we tested whether estrogen receptor (ER) signaling contributes to telomerase activation, an early event in prostate tumorigenesis. Following 17beta-estradiol (E(2)) treatment, both mRNA encoding the catalytic subunit of human telomerase (hTERT) and telomerase activity were promptly induced in human prostate normal epithelial cells, fresh explants from benign prostate hyperplasia, and prostate cancer explants and cell lines. Reporter expression studies and in vivo chromatin immunoprecipitation assays revealed E(2)-dependent hTERT promoter induction and showed that both ERalpha and ERbeta bound this sequence. Crucially, addition of the anti-estrogen 4-hydroxytamoxifen caused a differential recruitment in vivo of ERalpha and ERbeta onto the hTERT promoter and inhibited telomerase activity. Treatment with the aromatase inhibitor letrozole, which prevented testosterone-mediated interaction between ER and the hTERT estrogen response element, resulted in a negative regulation of telomerase activity. Thus, intracellular conversion of androgens to estrogens may contribute to the etiopathogenesis of prostate cancer. Given the present evidence for direct control of hTERT gene expression and telomerase activity in the prostate by the ER, we suggest that this transcriptional regulator represents a possible therapeutic target in prostate cancer.
UI - 12113054
AU - Gdor Y; Timme TL; Miles BJ; Kadmon D; Thompson TC
TI - Gene therapy for prostate cancer.
SO - Expert Rev Anticancer Ther 2002 Jun;2(3):309-21
AD - Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, Suite 2100, Houston, TX 77030, USA.
Prostate cancer is the most common noncutaneous cancer in man. When confined to the prostate it can be cured by radical prostatectomy or irradiation therapy. However, there are no curative therapies for locally advanced, recurrent or metastatic disease. Prostate cancer gene therapy has recently transition from preclinical studies to clinical trials with the goal of developing novel treatments for prostate cancer. The greatest challenge in treating advanced prostate cancer is therapeutic access to and the elimination of metastases. This review details two aspects of prostate cancer gene therapy, the types of delivery systems under development and specific categories of therapeutic genes available with an emphasis on the mechanism of action of specific gene therapy strategies.
UI - 11944990
AU - Chen H; Pong RC; Wang Z; Hsieh JT
TI - Differential regulation of the human gene DAB2IP in normal and malignant prostatic epithelia: cloning and characterization.
SO - Genomics 2002 Apr;79(4):573-81
AD - Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA.
Human DAB2IP (for DAB2 interaction protein) is a novel member of the RasGTPase-activating protein family. It interacts directly with DAB2, which suppresses growth of many cancer types. We demonstrated that DAB2IP is often downregulated in human prostate cancer cell lines. The predicted DAB2IP protein (967 amino acids) shares 94.2% homology with the rat DIP1/2 protein. We mapped the promoter of DAB2IP and studied its regulation in normal and malignant prostate cancer cells. This gene is located at 9q33.1-q33.3 and spans approximately 96 kb with 15 exons and 14 introns. The DAB2IP promoter does not contain any typical TATA box-evidenced by the presence of various RNAs with differential transcription starting sites. We further demonstrated that normal prostatic epithelial cells have elevated DAB2IP mRNA compared with cancer cells, which correlates with increased DAB2IP promoter activity. These data indicate that transcriptional regulation of DAB2IP is responsible for the downregulation of DAB2IP expression in prostate cancer cells.
UI - 12131293
AU - Valeri A; Cormier L; Moineau MP; Cancel-Tassin G; Azzouzi R; Doucet L;
TI - Baschet F; Cussenot I; L'Her J; Berthon P; Mangin P; Cussenot O; Morin JF; Fournier G Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives.
SO - J Urol 2002 Aug;168(2):483-7
AD - Service d'Urologie, Centre Hospitalier Universitaire, Brest Cedex, France.
PURPOSE: Targeted screening for prostate cancer in high risk families is generally suggested by ages 40 to 45 years in first degree relatives. We support this concept by reporting higher risk and earlier onset of the disease in these families. MATERIALS AND METHODS: We proposed serum prostate specific antigen (PSA) testing in 40 to 70-year-old first degree relatives of 435 patients with prostate cancer treated between allowed us to define the familial prostate cancer status of each patient as sporadic or familial. RESULTS: Of the 747 potential candidates 442 (59%) accepted into the study have been screened, including 240 who were 40 to 49 years old (mean age 44.8) and 202 who were 50 to 70 years old (mean age 57.4). Two of the 240 subjects (0.8%) had PSA greater than 4 ng./ml. in the 40 to 49-year-old group. Prostate biopsies were negative in 1 relative but diagnostic for prostate cancer in the other. In the 50 to 70-year-old group 25 of 202 subjects (12.4%) had a PSA of greater than 4 ng./ml. Prostate cancer was diagnosed in 9 individuals (4.5%), 9 had negative biopsy results, 1 died before biopsy and 6 refused biopsy. The proportion of relatives with PSA greater than 4 ng./ml. and prostate cancer detection was not different according to familial status (sporadic or familial) but it was significantly higher in first degree relatives with early onset prostate cancer in the family at ages younger than 65 years (p = 0.037 and 0.012, respectively). CONCLUSIONS: Our results emphasize the usefulness of PSA screening in high risk families, including those without obvious hereditary features. Furthermore, early onset prostate cancer is a significant risk factor for prostate cancer in first degree relatives.
UI - 12131363
AU - Lin HY; Shih A; Davis FB; Tang HY; Martino LJ; Bennett JA; Davis PJ
TI - Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line.
SO - J Urol 2002 Aug;168(2):748-55
AD - Medical Research Service, Stratton Veterans Affairs Medical Center, Department of Medicine, Albany Medical College and Wadsworth Center, New York State Department of Health, Albany, New York, USA.
PURPOSE: Resveratrol (Calbiochem, La Jolla, California) is a naturally occurring stilbene reported to cause apoptosis in various cultured cancer cells. In the current study the effect of resveratrol was determined in the androgen insensitive DU 145 prostate cancer cell line. Induction of apoptosis and activation of apoptosis related signal transduction pathways were measured. MATERIALS AND METHODS: DU 145 cells were treated with resveratrol and apoptosis was measured by determining nucleosome content. Activation of mitogen activated protein kinase (MAPK) (extracellular signal-regulated kinase 1/2), p53 content and serine-15 phosphorylation of p53 were measured by immunoblot. Electrophoretic mobility shift assay of p53 binding to DNA, and measurement of p21 and glyceraldehyde-3-phosphate dehydrogenase messenger RNA were also done. RESULTS: Resveratrol induced apoptosis in DU 145 cells. The stilbene activated MAPK and caused increased abundance of p53 and serine-15 phosphorylated p53. Resveratrol induced serine-15 phosphorylation of p53 was blocked by PD 98059 (Calbiochem), a MAPK kinase inhibitor, implicating MAPK activation in the phosphorylation of p53. PD 98059 also inhibited resveratrol induced apoptosis. These results suggest that apoptosis induction by resveratrol in DU 145 cells requires serine-15 phosphorylation of p53 by MAPK. Inhibition of MAPK dependent serine-15 phosphorylation resulted in reduced p53 binding to a p53 specific oligonucleotide on electrophoretic mobility shift assay. Pifithrin-alpha (Calbiochem), a p53 inhibitor, blocked resveratrol induced serine-15 phosphorylation of p53 and p53 binding to DNA. Resveratrol caused a p53 stimulated increase in p21 messenger RNA. Transfection of additional wild-type p53 into DU 145 cells induced apoptosis, which was further enhanced by resveratrol treatment. CONCLUSIONS: Resveratrol causes apoptosis in DU 145 prostate cancer cells. This action depends on the activation of MAPK, increase in cellular p53 content, serine-15 phosphorylation of p53 and increased p53 binding to DNA.
UI - 12140757
AU - Gnanapragasam VJ; Robson CN; Neal DE; Leung HY
TI - Regulation of FGF8 expression by the androgen receptor in human prostate cancer.
SO - Oncogene 2002 Aug 1;21(33):5069-80
AD - Prostate Research Group, School of Surgical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
Fibroblast growth factor 8 (FGF8) has been shown to play a key role in prostate carcinogenesis. It was initially cloned as an androgen induced protein in mouse mammary cancer SC3 cells. In this study, we examined if FGF8 was also regulated by the androgen receptor in human prostate cancer. FGF8b protein expression in resected clinical prostate cancer correlated closely with expression of the androgen receptor (AR). In the androgen sensitive CWR22 prostate xenograft, we observed up-regulation of FGF8b immunoreactivity in testosterone supplemented mice while castration markedly reduced its signal. Furthermore, FGF8b protein expression in AR positive LNCaP cells was similarly enhanced by androgens. The proximal promoter of the human FGF8 gene was cloned into a luciferase reporter construct (FGF8.luc). FGF8.luc activity in AR positive LNCaP and SC3 cells was increased 2.5-fold by androgens. In AR negative DU145 cells, maximal induction of FGF8.luc required both co-transfection of the AR and the presence of androgens. The anti-androgen bicalutamide completely abolished AR mediated FGF8.luc induction. Deletion constructs from FGF8.luc have further defined an active promoter region and an androgen responsive region. Nucleotide analysis of this androgen responsive region has revealed putative androgen response elements. Finally, using ChIP assays we confirmed in vivo interaction between the AR and the androgen responsive region of the FGF8 promoter. Taken together these data provide first evidence that expression of the mitogen FGF8 in prostate cancer is, at least in part, regulated by the androgen receptor at the transcriptional level.
UI - 12022038
AU - Wang L; McDonnell SK; Elkins DA; Slager SL; Christensen E; Marks AF;
TI - Cunningham JM; Peterson BJ; Jacobsen SJ; Cerhan JR; Blute ML; Schaid DJ; Thibodeau SN Analysis of the RNASEL gene in familial and sporadic prostate cancer.
SO - Am J Hum Genet 2002 Jul;71(1):116-23
AD - Department of Laboratory Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC). To confirm these findings, we screened 326 patients from 163 families with familial PC for potential germline mutations, by use of conformation-sensitive gel electrophoresis, followed by direct sequence analysis. A total of six variants were identified, including one intronic and five exonic changes (three missense and two silent alterations). There were no unequivocal pathogenic changes. To further test for potential associations between genes and increased risk for disease, the three missense polymorphisms (Ile97Leu, Arg462Gln, and Glu541Asp) were genotyped in 438 patients with familial PC and in 510 population-based control subjects. Association testing revealed no significant differences between patients and control subjects for either the Leu97 variant (chi(2) trend test = 1.42; P=.23) or the Asp541 variant (chi2=1.52; P=.22). However, significant differences were detected for the Arg462Gln genotypes (chi2=5.20; P=.02; odds ratio [OR] = 0.54; 95% confidence interval [CI] 0.32-0.91) when the genotype Gln/Gln was compared with Arg/Arg. In subset analyses, associations were also observed in the younger group (age at diagnosis =64 years) (P=.0008; OR=0.29; 95% CI = 0.13-0.66), in node-negative patients (P=.01; OR=0.48; 95% CI 0.27-0.84), patients with stage T(1)/T(2) disease (P=.008; OR=0.39; 95% CI 0.2-0.75), and patients with low-grade disease (P=.01; OR=0.40; 95% CI 0.20-0.78). To evaluate whether this variant was also associated with sporadic PC, we genotyped an additional 499 patients with sporadic PC. Differences in frequency were not detected between patients with sporadic disease and control subjects. However, the same association was observed between patients with familial disease and patients with sporadic disease for the entire group (chi2=4.82; P=.03), as well as in the subset analyses. These results suggest that polymorphic changes within the RNASEL gene may be associated with increased risk of familial but not sporadic PC.
UI - 11149418
AU - Chen Y; Hughes-Fulford M
TI - Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator, SREBP2.
SO - Int J Cancer 2001 Jan 1;91(1):41-5
AD - Laboratory of Cell Growth, University of California San Francisco and Veterans Affairs Medical Center, USA.
The low-density lipoprotein receptor (LDLR) pathway provides cells with essential fatty acids for prostaglandin E2 (PGE2) synthesis. Regulation of LDLR expression by LDL was compared between the human normal and cancer prostate cells using semi-quantitative RT-PCR and LDL uptake assays. LDLR mRNA expression and LDL uptake by LDLR were down-regulated in the presence of exogenous LDL or whole serum in the normal prostate cells, but not in the prostate cancer cells. Addition of exogenous cholesterol down-regulated both LDLR and a potent regulator of the ldlr promoter, sterol regulatory element binding protein 2 (SREBP2), in normal cells but not in cancer cells. PGE2 synthesis in prostate cancer cells was significantly increased in response to LDL. Our study suggests that over-production of LDLR is an important mechanism in cancer cells for obtaining more essential fatty acids through LDLR endocytosis, allowing increased synthesis of prostaglandins, which subsequently stimulate cell growth. The data also suggest that the sterol regulatory element and SREBP2 play a role in the loss of sterol feedback regulation in cancer cells.
UI - 11760786
AU - Grossmann ME; Wood M; Celis E
TI - Expression, specificity and immunotherapy potential of prostate-associated genes in murine cell lines.
SO - World J Urol 2001 Nov;19(5):365-70
AD - Department of Urology, Mayo Clinic, Rochester, MN 55905, USA. firstname.lastname@example.org
The TRAMP-C1 (C1) and TRAMP-C2 (C2) cell lines were derived from a prostate tumor that arose in a mouse from the transgenic adenocarcinoma mouse prostate (TRAMP) model. However, their similarity to primary prostate tumors and therefore their usefulness in immunotherapy studies has not been clearly defined. We showed using RT-PCR that these cell lines exhibited a variety of prostate-specific genes expressed by human prostate tumors that may be used as tumor-associated antigens for immunotherapy. Interestingly, several of these genes are also expressed in cell lines that are not prostatic in origin. The prostate cell lines were also shown to grow in an androgen-independent manner, to be capable of expressing MHC class I and to be susceptible to specific lysis by cytotoxic T lymphocytes. Therefore, these cell lines will provide us with the ability to evaluate immune responses to and tolerance of prostate-specific protein peptides in an animal model.
UI - 12109344
AU - Fowler JE Jr; Bigler SA
TI - Racial differences in prostate carcinogenesis. Histologic and clinical observations.
SO - Urol Clin North Am 2002 Feb;29(1):183-91
AD - Departments of Surgery and Urology, University of Mississippi School of Medicine, 2500 North State Street, Jackson, MS 39216, USA. email@example.com
Racial differences in the prevalence of HGPIN and in the Gleason score of local stage cancers indicate that clinically observed racial differences in cancer incidence and stage at diagnosis reflect racial variability in prostate carcinogenesis. Exploration of genetic, hormonal, nutritional, and behavioral differences in black and white men may provide insight into the fundamental mechanisms of prostatic carcinogenesis and cancer progression.
UI - 12153137
AU - Huang Y; Tang R; Dai J; Gu S; Zhao W; Cheng C; Xu M; Zhou Z; Ying K; Xi
TI - Y; Mao Y A novel human hydroxysteroid dehydrogenase like 1 gene (HSDL1) is highly expressed in reproductive tissues.
SO - Mol Biol Rep 2001;28(4):185-91
AD - State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, People's Republic of China.
We report the cloning and characterization of a novel human hydroxysteroid dehydrogenase like gene (HSDL1) located on human chromosome 16q24.2. The HSDL1 cDNA is 3407 base pair in length, encoding a 309 amino acid polypeptide related to human 17beta-HSD3. Northern blot reveals that the HSDL1 is highly expressed in testis and ovary. In situ hybridization indicates that the expression of HSDL1 is predominantly increased in the prostate cancer tissue compared with the normal prostate tissue, which suggests that the gene expression is important to the arising of prostate cancer.
UI - 12163397
AU - Park JH; Walls JE; Galvez JJ; Kim M; Abate-Shen C; Shen MM; Cardiff RD
TI - Prostatic intraepithelial neoplasia in genetically engineered mice.
SO - Am J Pathol 2002 Aug;161(2):727-35