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Abramson Cancer CenterNCI CANCERLIT® Search: Prostate Cancer, Hereditary - May 2002
National Cancer Institute®
Last Modified: May 1, 2002
Table of Contents
1
UI - 11959896
AU - Wojnowski L; Hustert E; Klein K; Goldammer M; Haberl M; Kirchheiner J;
TI -
Koch I; Klattig J; Zanger U; Brockmoller J
Re: modification of clinical presentation of prostate tumors by a novel
genetic variant in CYP3A4.
SO - J Natl Cancer Inst 2002 Apr 17;94(8):630-1; discussion 631-2
2
UI - 11929820
AU - Fluiter K; ten Asbroek AL; van Groenigen M; Nooij M; Aalders MC; Baas F
TI -
Tumor genotype-specific growth inhibition in vivo by antisense
oligonucleotides against a polymorphic site of the large subunit of
human RNA polymerase II.
SO - Cancer Res 2002 Apr 1;62(7):2024-8
AD - Neurozintuigen Laboratory, Academical Medical Center, 1105 AZ,Amsterdam,
the Netherlands.
Loss of heterozygosity (LOH) reduces genes to hemizygosity in cancer
cells and presents an absolute difference between normal and cancer
cells. The regions of LOH are usually much larger than the tumor
suppressor gene, which is lost, and are expected to contain genes that
are essential for cell survival. Single nucleotide polymorphisms (SNPs)
are the most common type of genetic variation in man, often giving rise
to two or more allelic forms of most genes. SNPs of essential genes that
are frequently affected by LOH can be used as a target for a novel
therapy against cancer cells with LOH. The SNPs can be targeted by
antisense oligonucleotides (ODNs) that will discriminate between two
alleles. We have designed allele-specific phosphorothioate ODNs against
the gene of the large subunit of RNA polymerase II (POLR2A), a gene
located in close proximity to the tumor suppressor gene p53, which
frequently shows LOH in cancer cells. This report shows that
phosphorothioate antisense ODNs directed against POLR2A can inhibit
tumor growth in vivo as efficiently as a well-described antitumor
antisense ODN directed against Ha-ras. In addition, we show that a
single bp mismatch can be sufficient to obtain allele-specific
inhibition of tumor growth, demonstrating that the effects observed are
true antisense effects.
3
UI - 11929841
AU - Vilenchik M; Raffo AJ; Benimetskaya L; Shames D; Stein CA
TI -
Antisense RNA down-regulation of bcl-xL Expression in prostate cancer
cells leads to diminished rates of cellular proliferation and resistance
to cytotoxic chemotherapeutic agents.
SO - Cancer Res 2002 Apr 1;62(7):2175-83
AD - Department of Medicine, Columbia University, College of Physicians and
Surgeons, New York, New York 10032, USA.
bcl-xL is a M(r) 26,000 bcl-2 homologue that is highly expressed in
prostate cancer cells. In previous studies, the down-regulation of its
expression by antisense oligonucleotides led to resistance. In this
work, the 445-bp 5' terminus of the bcl-xL cDNA was cloned in the
antisense orientation and stably transfected into DU145 and LNCaP
prostate cancer cells. In the DU145 (and to a lesser extent the LNCaP)
transfectants, phenotypic changes (versus mock-transfected cells)
included an increase in doubling time (from 36 to 175 h) in the clone in
which bcl-xL protein expression was 25% of control. The transfectants
did not demonstrate characteristic apoptotic changes, as demonstrated by
4',6-diamidino-2-phenylindole staining, lack of either DNA laddering,
caspase-3 activation, or poly(ADP)ribose and lamin cleavage, and the
absence of a significant sub-G(0) population. Cell cycle analysis
demonstrated an increase in a tetraploid population (from 28% to 66%),
as well as the appearance of a hypertetraploid population. Levels of
cIAP-1 protein were almost undetectable in the mock cells but increased
at least 25-fold in the DU145 transfectants. The down-regulation of
bcl-xL in both DU145 (and to a much lesser extent in LNCaP) cells led to
their resistance to cytotoxic agents, including docetaxel, mitoxantrone,
etoposide, vinblastine, and carboplatin. Reversion of bcl-xL expression
in stable DU145 transfectants to nearly the levels found in the
mock-transfected cells was accomplished by retroviral infection of the
cells with a bcl-xL sense cDNA under control of a prolific promoter.
This led to a dramatic increase in the growth rate and in BrdUrd
incorporation, as well as a sharp decrease in the expression of cIAP-1
protein. Overall, these findings highlight the adaptability of prostate
cancer cells to loss of bcl-xL and suggest that in addition to its
prosurvival role, bcl-xL protein may also be involved in the regulation
of the rate of cellular proliferation.
4
UI - 11895861
AU - Asamoto M; Hokaiwado N; Cho YM; Shirai T
TI -
Effects of genetic background on prostate and taste bud carcinogenesis
due to SV40 T antigen expression under probasin gene promoter control.
SO - Carcinogenesis 2002 Mar;23(3):463-7
AD - First Department of Pathology, Nagoya City University Medical School,
Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya City 467-8601, Japan.
masamoto@med.nagoya-cu.ac.jp
The incidence of prostate carcinomas in African-American men is greater
than in white men, indicating genetic factors are involved in risk of
this neoplasia. Recently, we have developed a transgenic rat model of
prostate cancer, featuring development of malignancies within 15 weeks
of age at very high incidence. Male transgenic rats with a
Sprague-Dawley genetic background were mated with wild-type females of
F344, Wistar and ACI strains. F1 male transgenic hybrids with female
Wistar and ACI rats had significantly lowered incidences of prostate
carcinomas. However, the serum level of testosterone, and expression of
the transgene, probasin, and the androgen receptor did not correlate
with the strain variation in tumor development. Furthermore,
immunohistochemical analysis of the SV40 Tag and the androgen receptor
also did not reveal any differences between the strains. The transgenic
rats additionally developed taste bud neuroblastomas at 100% incidence
and this was suppressed in F1 male transgenic offspring with the ACI,
but not the other strains. These results clearly show that genetic
background influences prostate carcinogenesis and taste bud
tumorigenesis in rats and that the present transgenic rats could provide
a good model to identify specific factors.
5
UI - 11920953
AU - Fu Z; Dozmorov IM; Keller ET
TI -
Osteoblasts produce soluble factors that induce a gene expression
pattern in non-metastatic prostate cancer cells, similar to that found
in bone metastatic prostate cancer cells.
SO - Prostate 2002 Apr 1;51(1):10-20
AD - Program in Immunology, School of Medicine, University of Michigan, Ann
Arbor, Michigan 48109, USA.
BACKGROUND: Progressive prostate cancer typically metastasizes to bone
where prostate cancer cells gain an osteoblast-like phenotype and induce
osteoblastic metastases through unknown mechanisms. To investigate the
biology of prostate cancer skeletal metastases, we compared gene
expression between the non-metastatic LNCaP cell line and its derivative
cell line C4-2B that metastasizes to bone. METHODS: Total RNA from LNCaP
and C4-2B cell lines was isolated and used to probe membrane-based gene
arrays (Comparison 1). Additionally, LNCaP cells were incubated in the
absence or presence of conditioned media (CM) from a human
osteoblast-like cell line (HOBIT) and total RNA from these cells was
used to probe gene arrays (Comparison 2). Differential expression of
genes was confirmed by RT-PCR. RESULTS: Of the 1,176 genes screened, 35
were differentially expressed between LNCaP and C4-2B cells (Comparison
1). HOBIT-CM induced differential expression of 30 genes in LNCaP cells
(Comparison 2). Interestingly, 19 genes that were differentially
expressed in C4-2B vs. LNCaP also displayed a similar expression pattern
in LNCaPs grown in HOBIT-CM. These genes are primarily involved in
motility, metabolism, signal transduction, tumorigenesis, and apoptosis.
CONCLUSIONS: These results suggest that osteoblasts produce soluble
factors that contribute to the progression of prostate cancer skeletal
metastases, including their transition to an osteoblast-like phenotype.
Additionally, these data provide targets to explore for further
investigations towards defining the biology of skeletal metastases.
Copyright 2002 Wiley-Liss, Inc.
6
UI - 11920954
AU - Wubah JA; Fischer CM; Rolfzen LN; Khalili M; Kang J; Green JE; Bieberich
TI -
CJ
Ventral prostate predominant l, a novel mouse gene expressed exclusively
in the prostate.
SO - Prostate 2002 Apr 1;51(1):21-9
AD - Department of Biological Sciences, University of Maryland, Baltimore
County, Baltimore, Maryland 21250, USA.
BACKGROUND: Despite the region-specific nature of human prostate
disease, there is a paucity of information regarding the molecular basis
of prostate regionalization and patterning. To elucidate genetic
mechanisms that underlie prostate growth and development, we
investigated differential gene expression in mouse prostate lobes.
METHODS: mRNA differential display analysis was used to identify
differentially expressed genes during development of ventral, anterior,
and dorsolateral prostate lobes. Differential gene expression was
confirmed by Northern blot analysis and RT-PCR. RESULTS: A novel gene,
Ventral prostate predominant1 (Vpp1) was identified. Vpp1 mRNA was
evident in all lobes but accumulated predominantly in the ventral
prostate, and was detected on postnatal day 7 through adulthood
exclusively in the prostate gland. The steady-state level of Vpp1 mRNA
decreased markedly in response to castration, suggesting androgen
regulation of Vpp1 expression. Analysis of TRAMP tumors demonstrated a
dramatic decrease in the level of Vpp1 mRNA. CONCLUSIONS: The spatial
distribution and early postnatal onset of Vpp1 expression is consistent
with a role for this gene in prostate regionalization. The absolute
prostate specificity of Vpp1 expression may allow this gene to serve as
a paradigm to study the molecular basis of gene expression that is
restricted exclusively to the prostate gland. Copyright 2002 Wiley-Liss,
Inc.
7
UI - 11920955
AU - Gsur A; Madersbacher S; Haidinger G; Schatzl G; Marberger M; Vutuc C;
TI -
Micksche M
Vitamin D receptor gene polymorphism and prostate cancer risk.
SO - Prostate 2002 Apr 1;51(1):30-4
AD - Division of Applied and Experimental Oncology, Institute of Cancer
Research, University of Vienna, Austria. andrea.gsur@univie.ac.at
BACKGROUND: 1,25-dihydroxyvitamin D, the active form of vitamin D,
exerts antiproliferative effect on prostatic cells, mediated through the
vitamin D receptor. In a case-control study, we examined whether the
vitamin D receptor (VDR) gene polymorphism in exon 9 could affect
prostate cancer susceptibility. METHODS: One hundred ninety newly
diagnosed prostate cancer patients and 190 age-matched men with benign
prostatic hyperplasia (BPH), in whom the presence of prostate cancer was
excluded clinically or histologically, were recruited for this study.
The VDR TaqI polymorphism was investigated by polymerase chain reaction
(PCR) following restriction fragment length polymorphism using DNA from
lymphocytes. Depending on the presence or absence of the TaqI
restriction site at the third position of codon 352, patients were
classified as TT, Tt, or tt. RESULTS: The frequency of the tt genotype
was not significantly different between prostate cancer patients (18%)
and controls (12%; P = 0.07). The odds ratio (OR), calculated relative
to individuals with the TT genotype was 1.76 (95% confidence limit (CL)
= 0.90-3.45). After stratification for Gleason score and prostate
specific antigen levels in a case-case comparison (n = 190), no
significant associations with the VDR genotypes were detectable either.
CONCLUSIONS: In this case-control study of Austrian Caucasians, no
statistically significant association of the VDR TaqI polymorphism and
prostate cancer risk was found. Copyright 2002 Wiley-Liss, Inc.
8
UI - 11920956
AU - Bharaj BB; Luo LY; Jung K; Stephan C; Diamandis EP
TI -
Identification of single nucleotide polymorphisms in the human
kallikrein 10 (KLK10) gene and their association with prostate, breast,
testicular, and ovarian cancers.
SO - Prostate 2002 Apr 1;51(1):35-41
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital,
Toronto, Ontario, Canada.
BACKGROUND: The KLK10 gene (also known as the normal epithelial
cell-specific 1 gene) is a member of the expanded human kallikrein gene
family. Recently, it has been reported that KLK10 is a tumor suppressor
gene and that its expression is downregulated in various forms of cancer
and cancer cell lines. KLK10 is also upregulated in ovarian cancer. We
thus hypothesized that the KLK10 gene may be a target for mutations in
various cancers. METHODS: We sequenced the five coding exons of the
KLK10 gene using genomic DNA from various tumors, normal tissues, and
blood, by PCR amplification and automated sequencing. RESULTS: In none
of the tumor-derived DNAs, we identified somatic mutations that could
inactivate this gene. However, we identified a prevalent germline single
nucleotide variation at codon 50 (exon 3) of this gene [GCC (alanine) to
TCC (serine)]. The GCC genotype was less prevalent in prostatic cancer
patients in comparison to control subjects (P = 0.027) but no
differences were seen with testicular, ovarian, and breast cancer. We
also identified four genetic variations in exon 4, at codons106 [GGC
(glycine) to GGA (glycine)], codon 112 [ACG (threonine) to ACC
(threonine)], codon 141 [CTA (leucine) to CTG (leucine)], and at codon
149 [CCG (proline) to CTG (leucine)]. None of these variations was
significantly different between normal subjects and cancer groups.
CONCLUSIONS: We found no evidence for somatic mutations of the KLK10
gene in cancers of the prostate, breast, ovary, and testis. The single
nucleotide variation at codon 50 appears to be associated with prostate
cancer risk. Copyright 2002 Wiley-Liss, Inc.
9
UI - 11920957
AU - Bondar VM; McConkey DJ
TI -
Anoikis is regulated by BCL-2-independent pathways in human prostate
carcinoma cells.
SO - Prostate 2002 Apr 1;51(1):42-9
AD - Department of Cancer Biology, University of Texas, M.D. Anderson Cancer
Center, Houston, Texas 77030, USA.
BACKGROUND: Loss of contact with the extracellular matrix (ECM) triggers
a specialized form of apoptosis known as "anoikis" in normal epithelial
cells. Dependence on adhesion to ECM is often lost in transformed cells,
and the degree of anchorage independence may vary in non-metastatic and
metastatic cancer cells. BCL-2 oncoprotein overexpression correlates
with the progression and metastases of prostate cancer. Materials and
Methods We studied anoikis in suspension cultures of PC-3 and LNCaP
prostate carcinoma cells selected for enhanced metastatic potential in
vivo and in PC-3 and LNCaP cells stably transfected with BCL-2.
Apoptosis-associated DNA fragmentation was measured by agarose gel
electrophoresis and propidium iodide staining and flow cytometry.
Expression of BCL-2 family polypeptides was determined by
immunoblotting. RESULTS: Non-metastatic PC-3P cells were significantly
more sensitive to anoikis than the metastatic PC-3 variants (PC-3M,
PC-3M-PRO-4, and PC-3M-LN-4), but anoikis resistance did not correlate
with metastatic potential in LNCaP-derived cell lines. Expression of
BCL-2 was higher in metastatic PC-3 and LNCaP subclones compared to
isogenic non-metastatic cells, but these levels were not affected by
anoikis. Enforced overexpression of BCL-2 did not protect either PC-3P
or LNCaP-PRO-5 cells from anoikis, even though it rendered them
resistant to thapsigargin and inhibited cytochrome c release.
Strikingly, cells that died of anoikis maintained their pretreatment
levels of BCL-2, whereas the cells that survived anoikis expressed much
lower levels of the protein. CONCLUSIONS: Sensitivity to anoikis is
regulated by BCL-2 independent mechanisms in LNCaP and PC-3 prostate
cancer cells. Copyright 2002 Wiley-Liss, Inc.
10
UI - 11920959
AU - Shi XB; Nesslinger NJ; Deitch AD; Gumerlock PH; deVere White RW
TI -
Complex functions of mutant p53 alleles from human prostate cancer.
SO - Prostate 2002 Apr 1;51(1):59-72
AD - Department of Urology, University of California, Davis, School of
Medicine, Sacramento, California 95817, USA.
BACKGROUND: Few studies have used multiple assays to examine the
functionality of mutant p53 in prostate cancer (CaP). We employed seven
functional assays to study 16 representative mutant p53 alleles, six
from localized and ten from metastatic CaP. METHODS: Yeast assays were
employed to determine loss of function (LOF), partial function (PF), and
dominant-negative status. Assays using p53-null Saos2 cells were used to
determine whether mammalian cells transfected with mutant p53 could
up-regulate the MDR-1 or PCNA promoters, alter IL-6 expression or confer
the ability to grow in soft agar. As a further test of gain of function
(GOF), p53-null PC3 cells stably transfected with these mutant p53
alleles were examined for cell cycle distributions. RESULTS: All 16
mutant p53 alleles demonstrated either total or partial LOF. All but one
allele also had at least one gain of function; however, the pattern of
GOF was different for each mutant allele. Alleles derived from both
localized and metastatic CaP had similar GOF characteristics; however,
only alleles from metastatic disease had significantly increased S-phase
fractions. CONCLUSIONS: Different mutant p53 alleles from CaP had
different, complex functional profiles. The lack of predictable patterns
for these alleles suggest that each mutation may uniquely affect p53
function. Copyright 2002 Wiley-Liss, Inc.
11
UI - 11865951
AU - Kay PA; Riehle DL; Cheville JC; Lohse CM; Pankratz VS; Hill EM; Sebo TJ
TI -
Comparison of quantitative histomorphometry and DNA ploidy in tissue
sections of prostate carcinoma.
SO - Anal Quant Cytol Histol 2002 Feb;24(1):7-14
AD - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
Minnesota 55905, USA.
OBJECTIVE: To examine the ability of quantitative histomorphometry to
predict DNA ploidy of prostate carcinoma in biopsy tissue sections
assigned after quantitation by nuclear digital image analysis. STUDY
DESIGN: Thirty-five diploid, 35 tetraploid and 35 aneuploid prostatic
carcinomas in biopsies, assessed by the CAS 200 image analyzer (Bacus
Laboratories, Lombard, Illinois, U.S.A.), were reevaluated by the Bacus
Laboratories Incorporated Slide Scanner, a microscope that quantifies
histologic images. Thirty-one histomorphometric features from cancer
cells were captured at 40 x magnification, averaged across tilesfor each
case and incorporated into a multivariate discriminant model to
determine which features predicted ploidy interpretation by nuclear
image analysis using the CAS 200. RESULTS: On average, 60 and 15 minutes
were required to perform nuclear image analysis and histomorphometry,
respectively. The multivariate discriminant model identified
configurable run length, difference variance, contrast, inverse
difference moment, sum entropy and diagonal variance as histomorphometry
features capable of distinguishing diploid from nondiploid tumors (P <
.05). Cross-validation studies showed the model correctly classified
74.3% of the diploid and 57.1% of the nondiploid cases. CONCLUSION:
Quantitative histomorphometry can predict the ploidy of prostate
carcinoma in biopsy tissue sections. Quantitative histomorphometry has
potential as a method of rapidly assessing DNA ploidy otherwise
earmarked for nuclear image analysis, resulting in savings of time and
expense.
12
UI - 11956160
AU - Tsubaki J; Hwa V; Twigg SM; Rosenfeld RG
TI -
Differential activation of the IGF binding protein-3 promoter by
butyrate in prostate cancer cells.
SO - Endocrinology 2002 May;143(5):1778-88
AD - Department of Pediatrics, School of Medicine, Oregon Health Sciences
University, 3181 Southwest Sam Jackson Park Road, Portland, OR
97201-3402, USA.
Sodium butyrate (NaB), a dietary micronutrient, is a potent growth
inhibitor that initiates cell differentiation in many cell types,
including prostate cancer cells. The molecular mechanisms by which these
effects occur remain largely unknown. In this study, we investigated the
effects of NaB on the expression of IGF binding protein (IGFBP)-3, a
known growth regulator, in two human prostate cancer cell lines (PC-3
and LNCaP). Treatment with NaB (0-10 mM) caused a dose-dependent
stimulation of IGFBP-3 mRNA expression and parallel increases in protein
levels. A specific histone deacetylase inhibitor, trichostatin A (TSA)
similarly induced IGFBP-3 expression, indicating that histone
hyperacetylation may be critical in the regulation of IGFBP-3
expression. To investigate the molecular mechanism of NaB-regulated
IGFBP-3 expression, 1.87 kb of the human IGFBP-3 gene promoter was
cloned into the pGL2-basic luciferase reporter vector. In both PC-3 and
LNCaP cells, NaB (10 mM) significantly increased luciferase activity 20-
to 30-fold, compared with the untreated control. However, using 5'
sequential deletion constructs of the IGFBP-3 promoter, the NaB response
sequences in the IGFBP-3 promoter were different in PC-3 and LNCaP
cells. Our studies identified a region, -75 to +69 from the start of
transcription (+1), that is fully inducible by NaB treatment in LNCaP
cells, but not in PC-3 cells. Unlike other well characterized
NaB-regulated genes, Sp1 DNA sequences are not involved in NaB
up-regulation of IGFBP-3 gene in LNCaP cells. Further deletion studies
identified two independent regions critical for NaB-induced
transactivation in LNCaP cells. These regions contain consensus binding
sites for p53 and GATA, respectively, but mutational analyses and gel
shift assays suggested that, while the p53 response element is required
for NaB responsiveness, neither p53 nor GATA are involved. In summary,
we have demonstrated that 1) NaB significantly up-regulates IGFBP-3 mRNA
and protein levels in PC-3 and LNCaP prostate cancer cells; and 2) novel
butyrate- responsive elements lacking consensus Sp1 sites are used in
LNCaP cells.
13
UI - 11870822
AU - Hsu L; Prentice RL; Stanford JL
TI -
Some further results on incorporating risk factor information in
assessing the dependence between paired failure times arising from
case-control family studies: an application to prostate cancer.
SO - Stat Med 2002 Mar 30;21(6):863-76
AD - Public Health Sciences Division, Fred Hutchinson Cancer Research Center,
1100 Fairview Avenue North, MP-665, P.O. Box 19024, Seattle, Washington
98109-1024, U.S.A. lih@fhcrc.org
In a typical case-control family study, detailed risk factor information
is often collected on cases and controls, but not on their relatives for
reasons of cost and logistical difficulty in locating the relatives. The
impact of missing risk factor information for relatives on estimation of
the strength of dependence between the disease risk of pairs of
relatives is largely unknown. In this paper, we extend our earlier work
on estimating the dependence of ages at onset between paired relatives
from case-control family data to include covariates on cases and
controls, and possibly relatives. Using population-based case-control
families as our basic data structure, we study the effect of missing
covariates for relatives and/or cases and controls on the bias of
certain dependence parameter estimators via a simulation study. Finally
we illustrate various analyses using a case-control family study of
early onset prostate cancer. Copyright 2002 John Wiley & Sons, Ltd.
14
UI - 11914183
AU - Arnold JT; Isaacs JJ
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.
15
UI - 11935317
AU - Chang BL; Zheng SL; Hawkins GA; Isaacs SD; Wiley KE; Turner A; Carpten
TI -
JD; Bleecker ER; Walsh PC; Trent JM; Meyers DA; Isaacs WB; Xu J
Polymorphic GGC repeats in the androgen receptor gene are associated
with hereditary and sporadic prostate cancer risk.
SO - Hum Genet 2002 Feb;110(2):122-9
AD - Center for Human Genomics, Wake Forest University School of Medicine,
Winton-Salem, NC 27157, USA.
Androgen receptor (AR) has long been hypothesized to play an important
role in prostate cancer etiology. Two trinucleotide repeat polymorphisms
(CAG and GGC repeats in exon 1 of the AR gene) have been investigated as
risk factors for prostate cancer in several studies. However, the
results are inconclusive, probably because of the variations of study
designs, characteristics of study samples, and choices of analytical
methods. In this study, we evaluated evidence for linkage and
association between the two AR repeats and prostate cancer by using the
following comprehensive approaches: (1) a combination of linkage and
association studies, (2) a test for linkage by parametric analysis and
the male-limited X-linked transmission/disequilibrium test (XLRC-TDT),
(3) a test for association by using both population-based and
family-based tests, and (4) a study of both hereditary and sporadic
cases. A positive but weak linkage score (HLOD=0.49, P=0.12) was
identified in the AR region by parametric analysis; however, stronger
evidence for linkage in the region, especially at the GGC locus, was
observed in the subset of families whose proband had < or = 16 GGC
repeats (HLOD=0.70, P=0.07) or by using XLRC-TDT ( z'=2.65, P=0.008).
Significantly increased frequencies of the < or = 16 GGC repeat alleles
in 159 independent hereditary cases (71%) and 245 sporadic cases (68%)
cases compared with 211 controls (59%) suggested that GGC repeats were
associated with prostate cancer ( P=0.02). Evidence for the association
between the < or = 16 GGC repeats and prostate cancer risk was stronger
with XLRC-TDT ( z'=2.66, P=0.007). No evidence for association between
the CAG repeats and prostate cancer risk was observed. The consistent
results from both linkage and association studies strongly implicate the
GGC repeats in the AR as a prostate cancer susceptibility gene. Further
studies on this polymorphism in other independent data sets and
functional analysis of the GGC repeat length on AR activity are
warranted.
16
UI - 11827456
AU - Stephan DA; Howell GR; Teslovich TM; Coffey AJ; Smith L; Bailey-Wilson
TI -
JE; Malechek L; Gildea D; Smith JR; Gillanders EM; Schleutker J; Hu P;
Steingruber HE; Dhami P; Robbins CM; Makalowska I; Carpten JD; Sood R;
Mumm S; Reinbold R; Bonner TI; Baffoe-Bonnie A; Bubendorf L; Heiskanen
M; Kallioneimi OP; Baxevanis AD; Joseph SS; Zucchi I; Burk RD; Isaacs W;
Ross MT; Trent JM
Physical and transcript map of the hereditary prostate cancer region at
xq27.
SO - Genomics 2002 Jan;79(1):41-50
AD - Cancer Genetics Branch, National Human Genome Research Institute,
National Institutes of Health, Bethesda, MD 20892, USA.
dstephan@cnmcresearch.org
We have recently mapped a locus for hereditary prostate cancer (termed
HPCX) to the long arm of the X chromosome (Xq25-q27) through a
genome-wide linkage study. Here we report the construction of an
approximately 9-Mb sequence-ready bacterial clone contig map of
Xq26.3-q27.3. The contig was constructed by screening BAC/PAC libraries
with markers spaced at approximately 85-kb intervals. We identified
overlapping clones by end-sequencing framework clones to generate 407
new sequence-tagged sites, followed by PCR verification of overlaps.
Contig assembly was based on clone restriction fingerprinting and the
landmark information. We identified a minimal overlap contig for genomic
sequencing, which has yielded 7.7 Mb of finished sequence and 1.5 Mb of
draft sequence. The transcriptional mapping effort localized 57 known
and predicted genes by database searching, STS content mapping, and
sequencing, followed by sequence annotation. These transcriptional units
represent candidate genes for HPCX and multiple other hereditary
diseases at Xq26.3-q27.3.
17
UI - 11847524
AU - Ribeiro ML; Santos A; Carvalho-Salles AB; Hackel C
TI -
Allelic frequencies of six polymorphic markers for risk of prostate
cancer.
SO - Braz J Med Biol Res 2002 Feb;35(2):205-13
AD - Centro de Biologia Molecular e Engenharia Genetica, Universidade
Estadual de Campinas, Campinas, SP, Brasil.
The aim of the present study was to evaluate the distribution of
polymorphisms for the androgen receptor (AR) (CAG, StuI, GGN), SRD5A2
(Ala49Thr, Val89Leu) and CYP17 (MspA1) genes that are considered to be
relevant for risk of prostate cancer. We studied 200 individuals from
two cities in the State of Sao Paulo, by PCR, PCR-RFLP and ASOH
techniques. The allelic frequencies of the autosomal markers and the
StuI polymorphism of the AR gene were very similar to those described in
most North American and European populations. In relation to the CAG and
GGN number of repeats, the study subjects had smaller repeat lengths
(mean of 20.65 and 22.38, respectively) than those described in North
American, European and Chinese populations. In the present study, 30.5%
of the individuals had less than 22 CAG repeats and 45.5% had less than
23 GGN repeats. When both repeat lengths are considered jointly, this
Brazilian population is remarkably different from the others. Further
studies on prostate cancer patients need to be conducted to assess the
significance of these markers in the Brazilian population.
18
UI - 11863411
AU - Zhang L; Adams JY; Billick E; Ilagan R; Iyer M; Le K; Smallwood A;
TI -
Gambhir SS; Carey M; Wu L
Molecular engineering of a two-step transcription amplification (TSTA)
system for transgene delivery in prostate cancer.
SO - Mol Ther 2002 Mar;5(3):223-32
AD - Department of Biological Chemistry, University of California, Los
Angeles School of Medicine, Los Angeles, California 90095-1737, USA.
Gene therapy is founded on the concept that tissue-specific promoters
can express heterologous genes for molecular imaging or therapeutic
applications. The engineering of cell-specific enhancers to improve
potency and the development of two-step transcriptional activation
(TSTA) approaches have significantly improved the efficacy of transgene
expression. Here we combine these technologies to create a robust,
titratable, androgen-responsive system targeted to prostate cancer
cells. Our "chimeric" TSTA system uses a duplicated variant of the
prostate-specific antigen (PSA) gene enhancer to express GAL4
derivatives fused to one, two, or four VP16 activation domains. We
targeted the resulting activators to cells with reporter templates
bearing one, two, or five GAL4 binding sites upstream of firefly
luciferase. We monitored activity via firefly luciferase assays in
transfected cell extracts and in live nude mice using a cooled
charge-coupled device (CCD) imaging system. In this system, we found
that firefly luciferase expression in prostate cancer cells can be
varied over an 800-fold range. We also found that a single plasmid
bearing the optimized enhancer, GAL4-VP16 derivative, and reporter
expressed firefly luciferase at 20-fold higher levels than the
cytomegalovirus enhancer. We discuss the implications of this strategy
and its application to molecular imaging and therapy.
19
UI - 11941539
AU - Rokman A; Ikonen T; Seppala EH; Nupponen N; Autio V; Mononen N;
TI -
Bailey-Wilson J; Trent J; Carpten J; Matikainen MP; Koivisto PA; Tammela
TL; Kallioniemi OP; Schleutker J
Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25,
in patients and families with prostate cancer.
SO - Am J Hum Genet 2002 May;70(5):1299-304
AD - Laboratory of Cancer Genetics, Institute of Medical Technology, Temepere
University, and Tempere University Hospital, Tempere, Finland.
annika.rokman@uta.fi
The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a
ribonuclease that mediates the antiviral and apoptotic activities of
interferons. The RNASEL gene maps to the hereditary-prostate-cancer
(HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to
harbor truncating mutations in two families with linkage to HPC1. Here,
we screened for RNASEL germline mutations in 66 Finnish patients with
HPC, and we determined the frequency of the changes in the index
patients from 116 families with HPC, in 492 patients with unselected
prostate cancer (PRCA), in 223 patients with benign prostatic
hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X,
was found in 5 (4.3%) of the 116 patients from families with HPC. This
was significantly higher (odds ratio [OR] =4.56; P=.04) than the
frequency of E265X in controls (1.8%). The highest mutation frequency
(9.5%) was found in patients from families with four or more affected
members. Possible segregation was detected only in a single family.
However, the median age at disease onset for E265X carriers was 11 years
less than that for noncarriers in the same families. In addition, of the
four missense variants found, R462Q showed an association with HPC
(OR=1.96; P=.07). None of the variants showed any differences between
controls and either patients with BPH or patients with PRCA. We conclude
that, although RNASEL mutations do not explain disease segregation in
Finnish families with HPC, the variants are enriched in families with
HPC that include more than two affected members and may also be
associated with the age at disease onset. This suggests a possible
modifying role in cancer predisposition. The impact that the RNASEL
sequence variants have on PRCA burden at the population level seems
small but deserves further study.
20
UI - 12002526
AU - Narayanan BA; Narayanan NK; Stoner GD; Bullock BP
TI -
Interactive gene expression pattern in prostate cancer cells exposed to
phenolic antioxidants.
SO - Life Sci 2002 Mar 1;70(15):1821-39
AD - Microarray Systems Laboratory, American Health Foundation, Valhalla, NY
10595, USA. bhagavat@mindspring.com
Dietary phenolic compounds are known to elicite vital cellular responses
such as cell cycle arrest, apoptosis and differentiation by activating a
cascade of molecular events. As there is an increasing interest to
improve the efficacy of these compounds for use as potential
chemopreventive agents, we wanted to understand the impact of phenolic
compounds on target genes in prostate cancer. In this study we used
human cDNA microarrays with 2400 clones consisting of 17 prosite motifs
to characterize alterations in gene expression pattern in response to
the phenolic antioxidants ellagic acid (EA) and resveratrol (RE). Over a
48-hr exposure of androgen - sensitive LNCaP cells to EA and RE, a total
of 593 and 555 genes respectively, showed more than a two fold
difference in expression. A distinct set of genes in both EA-and
RE-treated cells may represent the signature profile of phenolic
antioxidant-induced gene expression in LNCaP cells. Although extensive
similarity was found between effects of EA - and RE - responsive genes
in prostate cancer cells, out of 246 genes with overlapping responses,
25 genes showed an opposite effect. Quantitative RT-PCR was used to
verify and validate the differential expression of selected genes
identified from cDNA microarrays. In-depth analysis of the data from
this study provided insight into the alterations in the p53 - responsive
genes, p300, Apaf-1, NF-kBp50 and p65 and PPAR families of genes,
suggesting the activation of multiple signaling pathways that leads to
growth inhibition of LNCaP cells. This is a first study to look for
changes in a large number of human genes in response to dietary
compounds.
21
UI - 11839671
AU - Maruyama R; Toyooka S; Toyooka KO; Virmani AK; Zochbauer-Muller S;
TI -
Farinas AJ; Minna JD; McConnell J; Frenkel EP; Gazdar AF
Aberrant promoter methylation profile of prostate cancers and its
relationship to clinicopathological features.
SO - Clin Cancer Res 2002 Feb;8(2):514-9
AD - Hamon Center for Therapeutic Oncology Research, Department of Pathology,
University of Texas Southwestern Medical Center, 6000 Harry Hines
Boulevard, Dallas, TX 75390, USA.
PURPOSE: We investigated the aberrant methylation profile of prostate
cancers and correlated the data with clinical findings. EXPERIMENTAL
DESIGN: Gene promoter methylation was analyzed in 101 prostate cancer
samples. In addition, we analyzed 32 nonmalignant prostate tissue
samples, which included 25 with benign disease, benign prostatic
hypertrophy, or prostatitis, and 7 normal tissues adjacent to cancer.
The methylation status of 10 genes was determined. The methylation index
(MI) was calculated as a reflection of the methylated fraction of the
genes examined. RESULTS: Methylation percentages of the genes tested in
prostate cancers were: RARbeta, 53%; RASSF1A, 53%; GSTP1, 36%; CDH13,
31%; APC, 27%; CDH1, 27%; FHIT, 15%; p16(INK4A), 3%; DAPK, 1%; and MGMT,
0%. Methylation percentages in nonmalignant tissues were much lower. For
clinicopathological correlations, we divided the cancer cases into low
(6 or less) or high (7 or more) Gleason score (GS) groups, and into low
(8 ng/ml or less) or high (greater than 8 ng/ml) preoperative serum
prostate-specific antigen (PSA) groups. Methylation of RASSF1A, GSTP1,
RARbeta, and CDH13 genes was significantly more frequent in the high GS
group than in the low GS group. Methylation of RASSF1A, CDH1, and GSTP1
genes was significantly more frequent in the high PSA group than in the
low PSA group. The median MIs were significantly higher in the high GS
and the high PSA groups. According to the Spearman rank-correlation
test, there was significant correlation between MI and GS (coefficient =
0.43, P < 0.0001) and the preoperative serum PSA (coefficient = 0.37, P
= 0.0003). CONCLUSIONS: Our results indicate that the methylation
profile of prostate cancers correlates with clinicopathological features
of poor prognosis.
22
UI - 11896443
AU - Lee YJ; Lee H; Borrelli MJ
TI -
Gene transfer into human prostate adenocarcinoma cells with an
adenoviral vector: Hyperthermia enhances a double suicide gene
expression, cytotoxicity and radiotoxicity.
SO - Cancer Gene Ther 2002 Mar;9(3):267-74
AD - Department of Pharmacology and Cancer Institute, University of
Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. leeyj@msx.upmc.edu
We have previously developed a recombinant adenovirus containing a
fusion gene of Escherichia coli cytosine deaminase (CD) and herpes
simplex virus type 1 thymidine kinase (HSV-1 TK) controlled by a
cytomegalovirus (CMV) enhancer-promoter. This replication-incompetent
adenovirus effectively transduced the CD-TK gene into human prostate
adenocarcinoma DU-145 or PC-3 cells. Interestingly, heat shock at 41
degrees C for 4 hours elevated the level of CD-TK by approximately 5- to
20-fold at a multiplicity of infection (MOI) of 1. Heat-enhanced
expression of CD-TK promoted cytotoxicity by 23-, 9-, or 47-fold in the
presence of 50 microg/mL ganciclovir (GCV), 500 microg/mL
5-fluorocytosine (5-FC), or 50 microg/mL GCV+500 microg/mL 5-FC,
respectively, at an MOI of 1. Moreover, there was an increase in
radiosensitivity when adenovirus-infected cells were heated at 41
degrees C for 4 hours followed by irradiation in the presence of the
prodrugs. Virus+heat+1 microg/mL GCV treatment increased
radiosensitivity by a dose-modifying factor (DMF) of 2.2, whereas
virus+heat+10 microg/mL 5-FC exposure resulted in a DMF of 2.3.
Radiosensitization was clearly enhanced as a result of combined prodrug
exposure (DMF=4.4). Our results suggest that the efficiency in
expression of suicide genes from an adenoviral vector used for cytotoxic
anticancer therapy could be improved by combining heat treatment with
radiation therapy.
23
UI - 11912447
AU - Chu DC; Chuang CK; Fu JB; Huang HS; Tseng CP; Sun CF
TI -
The use of real-time quantitative polymerase chain reaction to detect
hypermethylation of the CpG islands in the promoter region flanking the
GSTP1 gene to diagnose prostate carcinoma.
SO - J Urol 2002 Apr;167(4):1854-8
AD - Department of Clinical Pathology and Division of Urology, Chang Gung
Memorial Hospital and School of Medical Technology, Chang Gung
University, Tao-Yuan, Taiwan, Republic of China.
PURPOSE: We developed a real-time, quantitative, methylation sensitive
polymerase chain reaction (PCR) protocol to analyze hypermethylation of
the CpG islands in the promoter region of the pi class
glutathione-S-transferase gene GSTP1 in prostate cancer tissue.
MATERIALS AND METHODS: A total of 21 prostate cancer and 72 benign
prostate hyperplasia (BPH) tissue samples were analyzed. Genomic DNA was
digested with restriction enzyme, followed by real-time quantitative PCR
amplification. Cycle threshold values were used to determine whether
cancer genome was present in these tissues. A cutoff cycle threshold
value of 35 was arbitrarily assigned. Samples with a cycle threshold of
35 or less were considered positive for prostate cancer. Conventional
nested PCR was also performed for comparison. RESULTS: The mean cycle
threshold values plus or minus standard deviation in prostate cancer and
BPH cases were 30.12 +/- 2.88 and 37.77 +/- 2.72, respectively. All
prostate cancer samples analyzed showed positive results, while 5 of the
72 BPH samples tested positive. Conventional nested PCR data indicated
that 19 of 21 prostate cancer cases were positive for the methylation
change, while 71 of 72 BPH cases tested negative. The test limitations
of real-time PCR and the nested PCR protocols were determined to be
0.048 and 0.64 ng. DNA, respectively. CONCLUSIONS: We established a
novel protocol for detecting the methylation change in the 5' regulatory
sequence flanking the GSTP1 gene. The sensitivity of this protocol was
superior to that of conventional nested PCR. The data also suggest that
this novel protocol may accurately discriminate prostate carcinoma from
BPH.
24
UI - 11912448
AU - Ni Z; Lou W; Lee SO; Dhir R; DeMiguel F; Grandis JR; Gao AC
TI -
Selective activation of members of the signal transducers and activators
of transcription family in prostate carcinoma.
SO - J Urol 2002 Apr;167(4):1859-62
AD - Department of Urology, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania, USA.
PURPOSE: Cytokines, hormones and growth factors use signal transducers
and activators of transcription (STAT) signaling pathways to control
various biological responses, including development, differentiation,
cell proliferation and survival. Constitutive activation of STATs has
been found in a wide variety of human tumors. In this study we examined
the activity of STATs in primary human prostate tissues. MATERIALS AND
METHODS: STAT activity was determined in 104 human primary prostate
tissues, including 42 tumors, 42 matched normal prostates adjacent to
tumors and 20 normal prostates from donors without cancer by
electromobility shift assay. RESULTS: Significant levels of activated
Stat4 and Stat6 were detected in primary prostate tissues. However,
little or no expression of active Stat1, Stat2 or Stat5 was detected in
primary prostate tissues. Significantly higher levels of constitutive
Stat6 activity were found in prostate carcinomas compared with levels in
normal tissue adjacent to tumors and normal prostates from donors
without prostate cancer. There was no significant difference in Stat6
activity in normal prostate tissues adjacent to tumors and normal
prostates from donors without prostate cancer. The levels of Stat4
activity varied but failed to yield statistically significant
differences among tumors, matched normal prostates adjacent to tumors
and normal prostates from donors without cancer. CONCLUSIONS: We have
previously shown that Stat3 is activated in prostate cancer. The results
of the current study demonstrate that in addition to Stat3, Stat6 is
selectively activated in prostate cancer.
25
UI - 11956072
AU - Luo J; Zha S; Gage WR; Dunn TA; Hicks JL; Bennett CJ; Ewing CM; Platz
TI -
EA; Ferdinandusse S; Wanders RJ; Trent JM; Isaacs WB; De Marzo AM
Alpha-methylacyl-CoA racemase: a new molecular marker for prostate
cancer.
SO - Cancer Res 2002 Apr 15;62(8):2220-6
AD - Department of Pathology, Brady Urological Institute, Johns Hopkins
University, School of Medicine, Baltimore, MD 21287, USA.
Identification of genes that are dysregulated in association with
prostate carcinogenesis can provide disease markers and clues relevant
to disease etiology. Of particular interest as candidate markers of
disease are those genes that are frequently overexpressed. In this
study, we describe a gene, alpha-methylacyl-CoA racemase (AMACR), whose
expression is consistently up-regulated in prostate cancer. Analysis of
mRNA levels of AMACR revealed an average up-regulation of approximately
9 fold in clinical prostate cancer specimens compared with normal.
Western blot and immunohistochemical analysis confirms the up-regulation
at the protein level and localizes the enzyme predominantly to the
peroxisomal compartment of prostate cancer cells. A detailed
immunohistochemical analysis of samples from 168 primary prostate cancer
cases using both standard slides and tissue microarrays demonstrates
that both prostate carcinomas and the presumed precursor lesion
(high-grade prostatic intraepithelial neoplasia) consistently scored
significantly higher than matched normal prostate epithelium; 88% of the
carcinomas had a staining score higher than the highest score observed
for any sample of normal prostate epithelium. Both untreated metastas
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