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NCI CANCERLIT^® Search: Prostate Cancer, Hereditary - June 2002

National Cancer Institute^®
Last Modified: June 1, 2002

Androgen receptor CAG repeats and prostate cancer.
Mapping and gene expression profile of the minimally overrepresented 8q24 region in prostate cancer.
Genome analysis yields mutations linked to hereditary prostate cancer.
Knowledge and beliefs among brothers and sons of men with prostate cancer.
Impact of prostate cancer screening on health-related quality of life in at-risk families.
Differentiation and stromal-induced growth promotion of murine prostatic tumors.
CAG polymorphic repeat lengths in androgen receptor gene among Japanese prostate cancer patients: potential predictor of prognosis after
Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer.
Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues.
Intermediate cells in normal and malignant prostate epithelium express c-MET: implications for prostate cancer invasion.
Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault.
Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages,
Prognostic significance of race on biochemical control in patients with localized prostate cancer treated with permanent brachytherapy:
Identification and functional characterization of a human GalNAc [alpha]2,6-sialyltransferase with altered expression in breast cancer.
I105V polymorphism and promoter methylation of the GSTP1 gene in prostate adenocarcinoma.
A polymorphism in the UDP-Glucuronosyltransferase 2B15 gene (D85Y) is not associated with prostate cancer risk.
BCL2 antisense transcripts decrease intracellular Bcl2 expression and sensitize LNCaP prostate cancer cells to apoptosis-inducing agents.
Hereditary prostate cancer: clinical characteristics and survival.
Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey.
Perspective: prostate cancer susceptibility genes.
Clinical and pathological significance of vitamin D receptor gene polymorphism for prostate cancer which is associated with a higher
Intragenic amplification and formation of extrachromosomal small circular DNA molecules from the PIP gene on chromosome 7 in primary
Identification of differentially expressed genes associated with androgen-independent growth of prostate cancer.
Worry and attitude of men in at-risk families for prostate cancer about genetic susceptibility and genetic testing.
Relative promoter strengths in four human prostate cancer cell lines evaluated by particle bombardment-mediated gene transfer.
Family history and prostate cancer screening with prostate-specific antigen.
Confirmation of the prostate cancer susceptibility locus HPCX in a set of 104 German prostate cancer families.
Upregulation of prostate specific membrane antigen/folate hydrolase transcription by an enhancer.
[Familial prostate carcinoma in Germany]
Effects of herbal preparation Equiguard on hormone-responsive and hormone-refractory prostate carcinoma cells: mechanistic studies.
Identification of an additional hypoxia responsive element in the glyceraldehyde-3-phosphate dehydrogenase gene promoter.
Up-regulation of p21(WAF1/CIP1) levels leads to growth suppression of prostate cancer cell lines.
Defining the region(s) of deletion at 6q16-q22 in human prostate cancer.

1
UI - 11994226
AU - Nelson KA; Witte JS
TI - Androgen receptor CAG repeats and prostate cancer.
SO - Am J Epidemiol 2002 May 15;155(10):883-90
AD - Department of Epidemiology and Biostatistics, Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106-4945, USA.
Prostate cancer is the most common nonskin malignancy and the second leading cause of cancer deaths among men in the United States. Prostate cancer ([Mendelian Inheritance in Man 176807]) has a complex etiology; presently, age, ethnicity, and family history are the most consistently reported risk factors associated with disease. Other potential risk and protective factors have also been suggested. Androgen, acting through the androgen receptor (AR) is helpful in preserving the normal function and structure of the prostate. The AR ([Mendelian Inheritance in Man 313700]) is a structurally conserved member of the nuclear receptor superfamily of ligand-activated transcription factors. Androgens, such as testosterone, are strong tumor promoters, and work with the AR to augment the effect of any carcinogens present and stimulate cell division. The CAG repeats encode long glutamine homopolymeric amino acid chains in the amino-terminal domain of the AR gene. The authors focus on CAG repeat length because recent research suggests that men with shorter AR CAG lengths (e.g., < or =22 repeats) are at a greater risk of developing prostate cancer than are those with longer variants. Among populations studied to date, African Americans appear to have the highest frequency of short CAG repeats. Several potential interactions have also been explored, including molecular interactions, androgen deprivation therapy, and prostate-specific antigen expression. CAG repeat length can be determined with high sensitivity and specificity. Presently, there is no recommended population screening for AR CAG repeat length.

2
UI - 12000731
AU - Tsuchiya N; Kondo Y; Takahashi A; Pawar H; Qian J; Sato K; Lieber MM;
TI - Jenkins RB Mapping and gene expression profile of the minimally overrepresented 8q24 region in prostate cancer.
SO - Am J Pathol 2002 May;160(5):1799-806
AD - Department of Urology, Mayo Clinic, Rochester, Minnesota 55905, USA.
We have recently reported that overrepresentation of 8q24 (c-myc) is associated with clinical progression in prostate cancer. In this study, we map the boundaries of the overrepresented region within 8q23-q24 using interphase fluorescent in situ hybridization analysis of paraffin-embedded prostate cancer specimens. One hundred primary prostate cancers and three prostate cancer cell lines were evaluated, and the minimally overrepresented region could be narrowed to the approximately 8.2-Mb region between D8S514 and H47317. This region includes c-myc and is wholly within 8q24. Eukaryotic translation initiation factor 3 subunit 3 does not seem to be overrepresented independent of c-myc in prostate cancer. The cell lines PC3 and DU145 have and do not have 8q24 overrepresentation, respectively. We then selected 39 expressed sequence tags (ESTs) within and surrounding the minimally overrepresented region and performed expression analysis using Northern blot hybridization. Five ESTs/genes including c-myc were overexpressed in both the PC3 cell line and DU145, but the PC3 to DU145 expression ratios were <2. Seven ESTs were overexpressed twofold or more in PC3 compared to DU145. This group included hyaluronan synthase 2, nephroblastoma-overexpressed gene, eukaryotic translation initiation factor 3 subunit 3, and an EST (R69368) encoding a hypothetical protein (BM009). These seven genes as well as c-myc are candidate target genes within the overrepresented 8q24 region and their overexpression may be associated with prostate cancer progression.

3
UI - 11851558
AU - Vastag B
TI - Genome analysis yields mutations linked to hereditary prostate cancer.
SO - JAMA 2002 Feb 20;287(7):827-8

4
UI - 12031377
AU - Cormier L; Kwan L; Reid K; Litwin MS
TI - Knowledge and beliefs among brothers and sons of men with prostate cancer.
SO - Urology 2002 Jun;59(6):895-900
AD - Departments of Urology and Health Services, University of California, Los Angeles, School of Medicine, Los Angeles, California, USA.
OBJECTIVES: To describe prostate cancer knowledge and beliefs, important predictors of screening behavior, in first-degree relatives of men with prostate cancer and to compare the knowledge with beliefs about familial risk. METHODS: We sent a letter to 837 men with prostate cancer to invite their brothers and/or sons aged 40 to 70 years to participate in the study. Their first-degree relatives who responded received a survey to explore their prostate cancer family history, prostate cancer knowledge, self-efficacy, barriers to screening, perceived benefits, perceived vulnerability, social support, and sociodemographic and medical characteristics. RESULTS: Of 139 participants (age 53 +/- 9 years), 92% were white, and 27% had more than one relative with prostate cancer. Ninety-eight percent of men answered at least one half of the knowledge questions correctly. Older men responded correctly more often than did younger men. Physician recommendations did not appear to be associated with better knowledge about familial risk. Among the 105 subjects (76%) who knew about familial risk, only 65 (62%) believed they themselves were at higher risk of prostate cancer than the average American man. Most of the beliefs were favorable to screening. CONCLUSIONS: Prostate cancer knowledge appeared high, although, surprisingly, familial risk was not the best understood domain. Physician recommendations were not associated with better knowledge about familial risk. Many men underestimated their own risk of developing prostate cancer, even among those with good knowledge about familial risk.

5
UI - 12031378
AU - Cormier L; Guillemin F; Valeri A; Fournier G; Cussenot O; Mangin P;
TI - Litwin MS Impact of prostate cancer screening on health-related quality of life in at-risk families.
SO - Urology 2002 Jun;59(6):901-6
AD - Department of Urology, CHU Nancy-Brabois, Vandoeuvre-les-Nancy, France.
OBJECTIVES: To describe the impact of prostate-specific antigen (PSA) screening on the health-related quality of life (HRQOL) and anxiety of men with a family history of prostate cancer. METHODS: We asked 334 brothers or sons of men with prostate cancer who agreed to undergo PSA testing to fill out HRQOL questionnaires. The questionnaires were the RAND SF-36 (generic HRQOL) and State-Trait Anxiety Inventory (anxiety-specific). Participants completed the questionnaires at the time of screening, while waiting for the results, and after receiving normal results. Sociodemographic and HRQOL variables were entered into a logistic regression model to identify factors associated with the deterioration of HRQOL, defined as a decrease of at least one standard error of measurement. Only men with normal PSA results were considered. RESULTS: Among 334 candidates, 273 underwent PSA measurement and 220 candidates with a PSA of 4 ng/mL or less returned completed questionnaires. Of these, in 20% their anxiety moderately deteriorated and in 20% their HRQOL minimally deteriorated during the screening process. Factors associated with HRQOL deterioration included age between 50 and 60 years, having more than two relatives with prostate cancer, an anxious personality, a high level of education, and having no children presently living at home. CONCLUSIONS: Screening with normal PSA results is accompanied by a minimally to moderate deterioration of HRQOL in some subjects. The identification of such individuals before screening provides opportunities to improve their HRQOL during the screening process.

6
UI - 11967952
AU - Salm SN; Takao T; Tsujimura A; Coetzee S; Moscatelli D; Wilson EL
TI - Differentiation and stromal-induced growth promotion of murine prostatic tumors.
SO - Prostate 2002 May 15;51(3):175-88
AD - Department of Cell Biology, MSB 634, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. salms01@endeavor.med.nyu.edu
BACKGROUND: We have derived a panel of p53-null prostatic "basal" and "luminal" epithelial cell lines and their ras transformed counterparts to study stromal/epithelial interactions and the properties of tumors arising from "basal" and "luminal" cells. METHODS: Previously derived normal murine prostatic "basal" epithelial (PE-B-1) and "luminal" epithelial (PE-L-1) cell lines were transformed with N-Ras. These lines and a spontaneously transformed "luminal" cell line were inoculated subcutaneously or orthotopically into athymic mice, alone or in combination with normal prostatic smooth muscle cells (SMC). RESULTS: All transformed lines formed subcutaneous tumors. SMC significantly enhanced the growth rate of the tumors arising from the "basal" and one of the "luminal" cell lines. The transformed "basal" line gave rise to tumors expressing both "basal" and "luminal" cytokeratins. CONCLUSIONS: Prostatic SMC promote the growth of transformed epithelial cells, suggesting that prostatic stroma may promote tumor development. Furthermore, transformed "basal" cells give rise to tumors containing "luminal" cells, suggesting that although most human tumors have a "luminal" phenotype, they may originate from transformed "basal" cells. Copyright 2002 Wiley-Liss, Inc.

7
UI - 11967956
AU - Suzuki H; Akakura K; Komiya A; Ueda T; Imamoto T; Furuya Y; Ichikawa T;
TI - Watanabe M; Shiraishi T; Ito H CAG polymorphic repeat lengths in androgen receptor gene among Japanese prostate cancer patients: potential predictor of prognosis after endocrine therapy.
SO - Prostate 2002 May 15;51(3):219-24
AD - Department of Urology, Graduate School of Medicine, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. hirosuzu@ho.chiba-u.ac.jp
BACKGROUND: Several investigators have examined the clinical significance of the length of the CAG repeat at the N-terminal region of the androgen receptor in the pathogenesis of prostate cancer. Because the clinical significance of CAG repeat length during the course of prostate cancer in Japanese patients is unknown, the present study analyzed CAG repeat length in relation to several potential clinical factors. MATERIALS AND METHODS: A total of 88 Japanese patients with prostate cancer and a control group of 53 patients with benign prostatic disease were enrolled in this study. The length of the CAG repeat was determined by PCR sequencing and analyzed in relation to several clinical factors. RESULTS: The length of the CAG repeat did not significantly differ between prostate cancer and benign prostatic disease. Although not statistically different with regard to clinical stage and serum PSA level, the CAG repeat length was associated with histological grade and age at diagnosis. In addition, the CAG repeat length in CR and in non CR patients significantly differed at 22.1 +/- 2.4 and 24.4 +/- 3.0, respectively (P = 0.0264), suggesting that the CAG repeat length can act as a molecular marker with which to predict response to endocrine therapy in stage D prostate cancer patients. CONCLUSIONS: A shorter CAG repeat length appears to predict a response to endocrine therapy, showing a positive prognostic value and indicating good prognosis in the metastatic stage of prostate cancer patients. Copyright 2002 Wiley-Liss, Inc.

8
UI - 11948965
AU - Segawa Y; Yoshimura R; Hase T; Nakatani T; Wada S; Kawahito Y; Kishimoto
TI - T; Sano H Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer.
SO - Prostate 2002 May 1;51(2):108-16
AD - Department of Urology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abenoku, Osaka 545-8585, Japan.
BACKGROUND: Recent studies have demonstrated that peroxisome proliferator activator-receptors (PPAR)-gamma is expressed in some cancer cells such as breast, lung, and gastric cancer, and its ligand induces growth arrest of these cancer cells through apoptosis. However, the expression and localization of PPARs in prostate have not been examined. In this study, PPARs expression was investigated in human prostate cancer (PC), prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues. METHODS: Tumor specimens were obtained from 156 patients with PC, 15 with PIN, 20 with BPH, and 12 patients with NP tissues. The expressions were investigated by RT-PCR and immunohistochemical methods. RESULTS: Immunoreactive PPAR-alpha and -beta were significantly apparent in PC tissues. Marked expressions of PPAR-alpha and -beta were also detected in PIN, BPH, and NP groups. However, very weak or no expression of immunoreactive PPAR-gamma was found in BPH and NP cases. In contrast, we found significant expression of immunoreactive PPAR-gamma in cancer cells in PC group and in PIN group. CONCLUSIONS: Our results demonstrated that PPAR-gamma is induced in PC, and suggest that PPAR-gamma ligands may mediate its own potent antiproliferative effect against PC cells through differentiation. Copyright 2002 Wiley-Liss, Inc.

9
UI - 11948967
AU - Yousef GM; Scorilas A; Chang A; Rendl L; Diamandis M; Jung K; Diamandis
TI - EP Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues.
SO - Prostate 2002 May 1;51(2):126-32
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
BACKGROUND: Kallikreins are a subgroup of serine proteases with diverse physiological functions. Many kallikrein genes are differentially expressed in various malignancies and prostate specific antigen (PSA; encoded by the KLK3 gene) is the best tumor marker for prostate cancer. Human glandular kallikrein (hK2; encoded by the KLK2 gene) is an emerging tumor marker for prostate cancer. KLK5 is a newly discovered human kallikrein gene which shares a high degree of homology and is located adjacent to KLK2 and KLK3 genes on chromosome 19q13.4. Like KLK2 and KLK3, the KLK5 gene is regulated by steroid hormones in the BT-474 breast cancer cell line. We have previously shown that KLK5 is differentially expressed in ovarian and breast cancer. METHODS: We compared the expression of KLK5 in 29 pairs of histologically confirmed normal and prostate cancer tissues by quantitative RT-PCR using the LightCycler technology. RESULTS: KLK5 expression was significantly lower in cancer tissues compared to their normal counterparts. Lowest levels of expression were found in T3 stage tumors compared with T1 and T2. Also, a significant negative correlation was found between Gleason score and KLK5 expression. CONCLUSIONS: KLK5 should be further studied as a potential new prognostic marker in prostate cancer, whose expression is negatively correlated with cancer aggressiveness. Copyright 2002 Wiley-Liss, Inc.

10
UI - 11948964
AU - van Leenders G; van Balken B; Aalders T; Hulsbergen-van de Kaa C; Ruiter
TI - D; Schalken J Intermediate cells in normal and malignant prostate epithelium express c-MET: implications for prostate cancer invasion.
SO - Prostate 2002 May 1;51(2):98-107
AD - Department of Pathology, University Medical Center St. Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands. G.vanleenders@pathol.azn.nl
BACKGROUND: Analysis of keratin (K) expression discriminates luminal (K18) and intermediate (K5/18) cells in prostate carcinoma, while basal (K5/14) cells are absent. Intermediate cells have been proposed as targets of malignant transformation in prostate cancer and precursors of androgen-independent tumor progression. We demonstrate localization of hepatocyte growth factor (HGF) receptor c-MET in intermediate cells in both normal and malignant prostate epithelium. METHODS: Receptor localization was analyzed using triple staining for c-MET, K5, K14, and K18. The percentage of strongly c-MET positive cells was determined in 15 prostate cancer patients undergoing androgen-deprivation and 14 patients without neo-adjuvant treatment. Effects of HGF were investigated on prostate cancer cell line DU145. RESULTS: c-MET expression in non-malignant epithelium was strong in intermediate cells absent in differentiated cells, and heterogeneous in basal cells. In prostate cancer, intermediate cells displayed high c-MET levels coupled with mild expression in differentiated cells. During androgen-deprivation, 7.6% of tumor cells revealed high c-MET expression compared to 1.7% without treatment (P = 0.02). Matrigel penetration of DU145 was 8.2 +/- 1.7 mm(2) after HGF stimulation compared to 3.6 +/- 2.4 mm(2) in controls (P < 0.02). CONCLUSIONS: Intermediate cells in normal and malignant prostate epithelium express high c-MET levels, indicating that they are prone to stromal invasion in prostate carcinoma. Copyright 2002 Wiley-Liss, Inc.

11
UI - 11914183
AU - Arnold JT; Isaacs JT
TI - Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault.
SO - Endocr Relat Cancer 2002 Mar;9(1):61-73
AD - National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health, 8 West Drive MSC 2669, Qtrs. 15B1, Bethesda, MD 20892-2669, USA. jarnold@mail.nih.gov
The acquisition of an androgen-independent phenotype by prostate cancer cells is presently a death sentence for patients. In order to have a realistic chance of changing this outcome, an understanding of what drives the progression to androgen independence is critical. We review here a working hypothesis based on the position that the development of androgen-independent epithelial cells is the result of a series of cellular and molecular events within the whole tissue that culminates in the loss of normal tissue-maintained growth control. This tissue includes the epithelial and stromal cells, the supporting extracellular matrix and circulating hormones. This review discusses the characteristics of these malignant cells, the role of stromal cells involved in growth and the differentiation of epithelial cells, and the role of the extracellular matrix as a mediator of the phenotypes of stromal and epithelial cells. In addition, environmental, neuroendocrine and immune factors that may contribute to disturbance of the fine balance of the epithelial-stromal-extracellular matrix connection are considered. While the goal of many therapeutic approaches to prostate cancer has been androgen ablation or targeting the androgen receptor (AR) of epithelial cells, these therapies become ineffective as the cells progress beyond dependence on androgen for growth control. Twenty years ago Sir David Smithers debated that cancer is the result of loss of tolerance within tissues and the organizational failure of normal growth-control mechanisms. This is precipitated by prolonged or abnormal demands for regeneration or repair, rather than of any inherent disorder peculiar to each of the individual components involved. He wrote "It is not the cell itself that is disorderly, but its relationship with the rest of the tissue". We have gained significantly large amounts of precise data on the effects of androgenic ablation on cancerous prostate cells and on the role of the AR in prostate cancer. The need has come to compile this information towards a perspective of dysregulation of tissue as a whole, and to develop experimental systems to address this broader perspective to find and develop therapies for treatment and prevention.

13
UI - 12023131
AU - Lee LN; Barnswell C; Torre T; Fearn P; Kattan M; Potters L
TI - Prognostic significance of race on biochemical control in patients with localized prostate cancer treated with permanent brachytherapy: multivariate and matched-pair analyses.
SO - Int J Radiat Oncol Biol Phys 2002 Jun 1;53(2):282-9
AD - Department of Radiation Oncology, Memorial Sloan-Kettering at Mercy Medical Center, Rockville Center, NY 11570, USA.
PURPOSE: To compare PSA relapse-free survival (PSA-RFS) between African-American (AA) and white American (WA) males treated with permanent prostate brachytherapy (PPB) for clinically localized prostate cancer. METHODS AND MATERIALS: One thousand eighty-one consecutive patients, including 246 African-Americans, underwent PPB with 103Pd or 125I, alone or with external beam radiation therapy between September create two identical cohorts of WA and AA males, based on the use of neoadjuvant androgen ablation (NAAD), pretreatment PSA, and Gleason score. Presenting characteristics were used to define risk groups, as follows: Low risk had PSA 10 or Gleason score >or=7, and high risk had PSA >10 and Gleason score >or=7. PSA-RFS was calculated using the Kattan modification of the ASTRO definition, and the log-rank test was used to compare Kaplan-Meier PSA-RFS curves. Univariate and multivariate analyses were performed to determine predictors of PSA-RFS. RESULTS: Overall, univariate analysis revealed that AA males at presentation had lower disease stage (p = 0.01), had lower Gleason scores (p = 0.017), were younger (p = 0.001), and were more likely to receive NAAD (p = 0.001) than their WA counterparts. There were no differences in pretreatment PSA, isotope selection, use of external beam radiation therapy, median follow-up, or risk group classification between AA and WA males. Pretreatment PSA and Gleason score were significant predictors of PSA-RFS in multivariate analysis, and race was not significant. There was no significant difference between the 5-year PSA-RFS for AA males (84.0%) and the matched cohort of WA males (81.2%) (p = 0.384). Race was not a predictor of 5-year PSA-RFS among patients treated with or without NAAD and within low-, intermediate-, and high-risk groups. CONCLUSION: Race is not an independent predictor of 5-year PSA-RFS in patients with localized prostate cancer treated with PPB. This result is consistent with other studies that also show that race does not contribute to differences in outcome after definitive therapies for localized prostate cancer.

14
UI - 11984005
AU - Sotiropoulou G; Kono M; Anisowicz A; Stenman G; Tsuji S; Sager R
TI - Identification and functional characterization of a human GalNAc [alpha]2,6-sialyltransferase with altered expression in breast cancer.
SO - Mol Med 2002 Jan;8(1):42-55
AD - Department of Pharmacy, School of Health Sciences, university of Patras, Greece. G.Sotiropoulou@upatras.gr
BACKGROUND: We sought to identify genes with altered expression during human breast cancer progression by applying mRNA comparisons of normal and tumor mammary cell lines with increasingly malignant phenotypes. The gene encoding a new sialyltransferase (STM) was found to be down-regulated in tumor cells. Abnormal expression and enzymatic activities of sialyltransferases in tumor cells result in the formation of tumor-associated carbohydrate antigens that can be used for the better understanding of the disease process and are applied for tumor diagnosis and immunotherapy. Altered glycosylation patterns of the MUC1 mucin, in particular, is a target antigen for immunotherapy of breast and other cancers. MATERIALS AND METHODS: Total RNAs from multiple normal mammary epithelial cell strains and tumor cell lines were compared by differential display and the differential expression of selected cDNAs was confirmed by Northern analyses. Recombinant STM was expressed in COS-7 cells. The substrate and linkage specificity of STM was examined using various oligosaccharides and O-glycosylated proteins as acceptor substrates. The chromosomal localization of the SIATL1 gene was assigned by somatic cell hybrid analysis. RESULTS: A human sialyltransferase gene was identified by differential display as being down-regulated in breast tumor cell lines as compared to normal mammary epithelial cell strains, and the corresponding full-length cDNA (stm) was cloned. The encoded protein of 374 amino acid residues contained the L- and S-sialylmotifs, two catalytic regions conserved in all functional sialyltransferases. Recombinant STM is an active GalNAc alpha2,6-sialyltransferase with Gal beta 1,3 GalNAc-O-Ser/Thr and (+/- Neu5Ac alpha 2,3) Gal beta 1,3GalNAc-O-Ser/Thr acceptor specificity. The SIATL1 gene, encoding STM, was mapped to the long arm of human chromosome 17 at q23-qter, a region that is nonrandomly deleted in human breast cancers. However, Southern analyses indicated that SIATL1 is usually not grossly rearranged in breast tumors. Northern analyses showed that the gene was widely expressed in normal human tissues, as well as in normal breast and prostate epithelial cell lines, but significantly down-regulated or absent in corresponding tumor cell lines. CONCLUSIONS: Our findings suggest that aberrant expression of STM sialyltransferase in tumors could be a feature of the malignant phenotype. In breast cancers, the MUC1 mucin is overexpressed and contains shorter O-glycans as compared to the normal mucin. Because STM catalyzes the synthesis of O-glycans, cloning and characterization of its substrate specificity will contribute to the understanding of the molecular mechanisms underlying the aberrant glycosylation patterns of O-glycans and the formation of mucin-related antigens in human breast cancers.

15
UI - 12010858
AU - Jeronimo C; Varzim G; Henrique R; Oliveira J; Bento MJ; Silva C; Lopes
TI - C; Sidransky D I105V polymorphism and promoter methylation of the GSTP1 gene in prostate adenocarcinoma.
SO - Cancer Epidemiol Biomarkers Prev 2002 May;11(5):445-50
AD - Department of Pathology, Portuguese Institute of Oncology, 4200-072 Porto, Portugal. carmenjeronimo@netc.jp
The GSTP1 gene encodes for an enzyme, glutathione S-transferase pi (GSTpi),involved in detoxification of carcinogens. An aminoacid substitution (I105V) in GSTP1 produces a variant enzyme with lower activity and less capability of effective detoxification. This variant GSTP*B allele has been associated with a propensity to develop several neoplasms. Because GSTP1 promoter hypermethylation and inactivation of GSTpi expression is a frequent alteration in prostate carcinoma, we hypothesized that this somatic epigenetic modification could obviate any reduced enzyme activity caused by the germ-line polymorphism. We tested for the GSTP1 genotype in a population of prostate cancer patients, and in a control group composed of patients with benign prostatic hyperplasia (BPH) and healthy blood donors. Tissue samples from the 105 prostate cancer cases (105 adenocarcinomas and 34 prostatic intraepithelial neoplasia lesions), and from 43 BPH patients were tested for GSTP1 hypermethylation by methylation-specific PCR. GSTpi protein expression was assessed by immunohistochemistry. No significant effect on prostate cancer risk was detectable for GSTP1 genotype compared with the control population (odds ratio, 1.02; 95% confidence interval, 0.59-1.75). Moreover, no association was found between this genotype and tumor or BPH methylation status. Patients with unmethylated carcinomas did not disclose significant differences in genotypic distribution compared with the control population. In adenocarcinoma, a strong association (P < 0.00001) between GSTP1 promoter hypermethylation and loss of GSTpi expression was observed; however, this trend was not retained in prostatic intraepithelial neoplasia or BPH lesions. Although the GSTP1 polymorphism is not associated with altered susceptibility to prostate cancer, somatic promoter hypermethylation is an effective, but not the only, cause of decreased GSTpi function.

16
UI - 12010866
AU - Gsur A; Preyer M; Haidinger G; Schatzl G; Madersbacher S; Marberger M;
TI - Vutuc C; Micksche M A polymorphism in the UDP-Glucuronosyltransferase 2B15 gene (D85Y) is not associated with prostate cancer risk.
SO - Cancer Epidemiol Biomarkers Prev 2002 May;11(5):497-8
AD - Division of Applied and Experimental Oncology, Institute of Cancer Research, University of Vienna, Austria. andrea.gsur@univie.ac.at

17
UI - 11776759
AU - Shi XB; Gumerlock PH; Muenzer JT; deVere White RW
TI - BCL2 antisense transcripts decrease intracellular Bcl2 expression and sensitize LNCaP prostate cancer cells to apoptosis-inducing agents.
SO - Cancer Biother Radiopharm 2001 Oct;16(5):421-9
AD - Dept of Urology, University of California, Davis, School of Medicine, 4860 Y Street, Suite 3500, Sacramento, CA 95817, USA.
Prostate cancer (CaP) is the most commonly diagnosed cancer of aging men and the second leading cause of male cancer death in the United States. At present, no effective therapy is available for treating hormone independent CaP. Since Bcl2 is believed to play a role in protecting CaP cells from apoptosis, we investigated the effects of down-regulating Bcl2 expression on CaP cells. Genetically engineered LNCaP sublines were established by stably transfecting LNCaP cells with BCL2 antisense (BCL2-AS) transcript-expressing plasmids. Western blotting analysis showed that intracellular Bcl2 protein was decreased by 50-60% in BCL2-AS-transfected LNCaP cells. Expression of the antisense transcripts resulted in 50% growth inhibition of LNCaP cells in response to androgen withdrawal and markedly sensitized these cells to Adriamycin-induced apoptosis. These results suggest that down-regulation of Bcl2 protein using BCL2-AS transcripts could be exploited for improved treatment of advanced CaP.

19
UI - 10815699
AU - Hawk E; Breslow RA; Graubard BI
TI - Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey.
SO - Cancer Epidemiol Biomarkers Prev 2000 May;9(5):523-7
AD - Gastrointestinal and Other Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland 20892-7322, USA. eh51p@nih.gov
Male pattern baldness (MPB) and prostate cancer are common in American males; however, MPB is clinically observable decades earlier. Aging, androgens, and heritability are risk factors for both conditions. We prospectively studied the association between MPB and clinical prostate cancer in a cohort representative of the United States male population. A total of 4,421 men 25-75 years old without a history of prostate cancer were examined for baldness in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey. Participants were followed from baseline (1971-1974) through 1992. Incident cases of prostate cancer were identified by interviews, medical records, and death certificates. Age-standardized incidence rates and proportional hazards models were used to examine the association between MPB and clinical prostate cancer. Prostate cancer was diagnosed in 214 subjects over 17-21 years of follow-up. The age-standardized incidence of prostate cancer was greater among men with baldness at baseline (17.5 versus 12.5 per 10,000 person-years). The adjusted relative risk for prostate cancer among men with baldness was 1.50 (95% confidence interval, 1.12-2.00) and was similar regardless of the severity of baldness at baseline and was independent of other risk factors, including race and age. MPB seems to be a risk factor for clinical prostate cancer.

20
UI - 12021166
AU - Simard J; Dumont M; Soucy P; Labrie F
TI - Perspective: prostate cancer susceptibility genes.
SO - Endocrinology 2002 Jun;143(6):2029-40
AD - Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Laval University, Quebec City, G1V 4G2, Canada. Jacques.Simard@crchul.laval.ca
In many developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal, and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that association of candidate genetic markers to this multifactorial malignancy is more difficult than the identification of susceptibility genes for some common cancers such as breast, ovary, and colon cancer. Several reasons may explain such a difficulty: 1) prostate cancer is diagnosed at a late age, thus often making it impossible to obtain DNA samples from living affected men for more than one generation; 2) the presence within high-risk pedigrees of phenocopies, associated with the lack of distinguishing features between hereditary and sporadic forms; and 3) the genetic heterogeneity of this complex disease along with the accompanying difficulty of developing appropriate statistical transmission models taking into account simultaneously multiple susceptibility genes, frequently showing moderate or low penetrance. Despite the localization of seven susceptibility loci, there has been limited confirmatory evidence of linkage for currently known candidate genes. Nonetheless, the discovery of the first prostate cancer susceptibility gene characterized by positional cloning, ELAC2 was achieved taking advantage of the Utah Family Resource. Moreover, common missense mutations in the ELAC2 gene were found to be significantly associated with an increased risk of diagnosis of prostate cancer in some studies. More recently, recombination map-ping and candidate gene analysis were used to map several genes, including the 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL) gene, to the critical region of HPC1. Two deleterious mutations in RNASEL segregate independently with the disease in two of the eight HPC1-linked families. Additional studies using larger cohorts are needed to fully evaluate the role of these two susceptibility genes in prostate cancer risk. Although a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, some of the familial risks may be due to shared environment and more specifically to common low-penetrance genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action, led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants, such as those found in 5alpha-reductase type 2 and AR genes.

21
UI - 11789558
AU - Hamasaki T; Inatomi H; Katoh T; Ikuyama T; Matsumoto T
TI - Clinical and pathological significance of vitamin D receptor gene polymorphism for prostate cancer which is associated with a higher mortality in Japanese.
SO - Endocr J 2001 Oct;48(5):543-9
AD - Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
The purpose of this study was to investigate the TaqI vitamin D receptor (VDR) polymorphism in both Japanese prostate cancer patients and Japanese noncancer controls in order to determine if an association exists between VDR genotype with clinical and pathological risk of prostate cancer patients. This study involved 115 patients with prostate cancer and 133 male age-matched noncancer controls genotyped for a previously described TaqI restriction fragment length polymorphism (RFLP) at codon 352 in exon 9 of the VDR gene. Products were digested into T allele or t allele according to the absence or presence of TaqI restriction site with individuals being classified as TT, Tt, or tt. The genotype tt was higher among the control group (6.0%) compared to the patients with prostate cancer (1.8%), but not so (OR=0.28; 95%o CI, 0.06-1.33; p=0.081). In addition, the genotype TT was statistically higher among patients with locally advanced or metastatic disease (T3/T4/NI/M1) compared to controls (OR=2.52; 95%o CI, 1.21-5.27; p=0.009). Lastly, the genotype TT was statistically higher among patients with poorly differentiated adenocarcinoma compared to controls (OR=5.38; 95%o CI, 1.57-18.50; p=0.002). These data demonstrate that VDR genotype plays an important role in determining the risk of more clinically advanced and pathologically aggressive prostate cancer which is associated with a higher mortality rate in Japanese men.

22
UI - 11992405
AU - Autiero M; Camarca A; Ciullo M; Debily MA; El Marhomy S; Pasquinelli R;
TI - Capasso I; D'Aiuto G; Anzisi AM; Piatier-Tonneau D; Guardiola J Intragenic amplification and formation of extrachromosomal small circular DNA molecules from the PIP gene on chromosome 7 in primary breast carcinomas.
SO - Int J Cancer 2002 May 20;99(3):370-7
AD - Genetique Moleculaire et Biologie du Developpement, Centre National de la Recherche Scientifique, Villejuif, France.
The PIP gene is expressed in exocrine glands and, in pathologic conditions, in breast cysts and breast cancers exhibiting apocrine features. It is localized on the long arm of chromosome 7, a region frequently alterated in mammary tumors. We previously described an abnormal restriction pattern of the PIP gene in 33% of prostate carcinomas analyzed. Here, we analyze the structure of the PIP gene in primary breast carcinomas. We report that part of the 3' end, including exon 3, intron C, two-thirds of exon 4 and a small portion of intron B, is amplified and involved in the formation of extrachromosomal spcDNA molecules in 3/14 (21.4%) breast cancers analyzed. The involvement of a well-defined intragenic region of a gene in the formation of spcDNA appears to be unprecedented. Since spcDNA has been suggested to serve as an enhancer of genetic instability, the PIP gene may be the target of genomic variability processes in breast cancer. Copyright 2002 Wiley-Liss, Inc.

23
UI - 11987153
AU - Mohler JL; Morris TL; Ford OH 3rd; Alvey RF; Sakamoto C; Gregory CW
TI - Identification of differentially expressed genes associated with androgen-independent growth of prostate cancer.
SO - Prostate 2002 Jun 1;51(4):247-55
AD - Department of Surgery, Division of Urology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599, USA. jmohler@med.unc.edu
BACKGROUND: The human prostate cancer xenograft, CWR22, similar to most human prostate cancers, regresses after castration and recurs several months after the removal of androgen. Genes uniquely associated with proliferation were identified by comparison of tumors that exist in androgen absence but differ in proliferative capacity. METHODS: cDNA libraries from CWR22 tumors from 20-day castrate mice (proliferation undetectable) and recurrent CWR22 tumors (proliferation rate similar to androgen-dependent CWR22) were compared to evaluate the possibility that proliferation is triggered by either gain of function or loss of suppression. Differentially expressed genes were evaluated further for their temporal association with the onset of cellular proliferation using northern and western analysis and immunohistochemistry of a series of CWR22 tumors that spanned the transition from androgen-dependent to recurrent growth. RESULTS: Subtractive hybridization identified 11 candidate genes from among 1,057 clones examined. Northern analysis confirmed differential expression of 8 genes. Western analysis revealed an association between tomoregulin, translation elongation factor-1 alpha (EF-1 alpha), Mxi-1, and thioredoxin-binding protein 2/vitamin D up-regulated protein, and the onset of recurrent growth. Immunohistochemistry revealed expression of tomoregulin, EF-1 alpha, Mxi-1, and thioredoxin reductase-1 coincidental with the onset of cellular proliferation on day 120 after castration. CONCLUSIONS: One or more of these genes may represent an appropriate target to prevent, delay or treat recurrent prostate cancer. Copyright 2002 Wiley-Liss, Inc.

24
UI - 11987156
AU - Cormier L; Valeri A; Azzouzi R; Fournier G; Cussenot O; Berthon P;
TI - Guillemin F; Mangin P Worry and attitude of men in at-risk families for prostate cancer about genetic susceptibility and genetic testing.
SO - Prostate 2002 Jun 1;51(4):276-85
AD - Department of Urology, CHU Nancy-Brabois, Vandoeuvre-les-Nancy, France. l.cormier@chu-nancy.fr
BACKGROUND: The aim of this study was to evaluate worry about genetic susceptibility and the attitude of men with family history of prostate cancer (CaP) toward genetic testing. METHODS: Three hundred seventy-five eligible first-degree relatives (FDR) of men with CaP, were asked to participate in a screening and to fill out a survey covering the worry about genetic susceptibility and interest in genetic testing. RESULTS: Of the 375 candidates contacted, 277 completed the survey, and had undergone PSA measurement. Sixty-four percent worried a little or not at all about inherited predisposition to CaP, while the remainder worried a lot or extremely. The candidates who worried a lot or extremely were men with high levels of durable anxiety disposition (STAI trait), who had undergone a previous screening procedure and men with sons. Ninety-eight percent of men expressed their interest in undergoing genetic testing. The most motivated candidates to have the test done were men with several relatives with CaP. CONCLUSIONS: The level of worry about genetic susceptibility was low and there was a concrete interest in genetic testing in FDR of men with CaP. This interest increased with the number of CaP in the family. Copyright 2002 Wiley-Liss, Inc.

25
UI - 11987157
AU - Zhang S; Gu J; Yang NS; Kao C; Gardner TA; Eble JN; Cheng L
TI - Relative promoter strengths in four human prostate cancer cell lines evaluated by particle bombardment-mediated gene transfer.
SO - Prostate 2002 Jun 1;51(4):286-92
AD - Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
BACKGROUND: The particle bombardment (gene gun) method for gene transfer provides a new and efficient means for transfection of various cell types in culture. In this study we evaluate its application to human prostate tumor cells. METHODS: Transient expression of the firefly luciferase gene driven by five viral and five cellular promoters was assessed after in vitro gene transfer using the gene gun method. The relative strengths of these promoters were quantitatively determined in four different human prostate tumor cell lines: DU145, PC-3, LNCaP, and CWR22Rv1 cells. In situ histochemical staining of cells, transfected with bacterial beta-galactosidase cDNA as a reporter gene, was also performed to evaluate the transfection efficiency. Time course of gene expression was determined using the luciferase reporter gene. RESULTS: The peak levels of transient expression of firefly luciferase are observed within 24 hr after gene transfer. Sustained but reduced luciferase levels were also detected as long as 5 days post transfection. Up to 35% of bombarded cells in vitro were found to express transgenic beta-galactosidase activity. Among tested viral promoters, cytomegalovirus early enhancer/promoter activity was observed to confer consistently the highest activity in each test cell line, whereas phosphoglycerate kinase gene promoter possessed the highest activity among the cellular promoters tested. CONCLUSIONS: The particle bombardment gene-transfer technology can be effectively employed as an efficient method for in vitro gene-transfer into prostate tumor cells. The characterization of relative promoter strength and preference may be useful for future studies of cancer gene therapy approaches. Copyright 2002 Wiley-Liss, Inc.

26
UI - 12039927
AU - Makinen T; Tammela TL; Stenman UH; Maattanen L; Rannikko S; Aro J;
TI - Juusela H; Hakama M; Auvinen A Family history and prostate cancer screening with prostate-specific antigen.
SO - J Clin Oncol 2002 Jun 1;20(11):2658-63
AD - Fin

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