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Abramson Cancer CenterNCI CANCERLIT® Search: Prostate Cancer, Hereditary - March 2002
National Cancer Institute®
Last Modified: March 1, 2002
Table of Contents
1
UI - 11712084
AU - Kasahara K; Taguchi T; Inoue K; Shuin T; Kariya S; Yoshida S; Furihata M
TI -
Early reduction in the aneuploidy at chromosomes 7 and 8 are
significantly correlated with clinical effect in high-dose rate
brachytherapy with external beam radiotherapy in localized prostate
cancer.
SO - Int J Mol Med 2001 Dec;8(6):667-73
AD - Department of Urology, Kochi Medical School, Nankoku, Kochi 783-8505,
Japan. kasahara@med.kochi-ms.ac.jp
Although reduction in the serum prostate specific antigen (PSA)
correlates with clinical outcome for high dose rate Iridium-192 (HDR
Ir-192) brachytherapy, it takes a long latency period. We investigated
numerical chromosome changes of prostatic cancer during the pre- and
post-treatment periods of HDR Ir-192 brachytherapy (and external beam
radiotherapy), using fluorescence in situ hybridization (FISH) to clear
the effect of treatment in early phase. Transitional changes in the
frequency of aneuploidy for chromosomes 7, 8, 10, 12, 16, X, and Y in
prostate cancer during the pre- and post-treatment periods were
observed. Gains of chromosomes 7, 8 and 12 were noted in the
pre-treatment samples (4 out of 12 cases in chromosomes 7 and 8; 1 out
of 12 cases in chromosome 12), while a notable reduction in the number
of cells with extra copies of these chromosomes was observed in
post-treatment specimens. This change appears earlier than the reduction
in the value of prostate specific antigen (PSA) and strongly reflects
the effect of HDR brachytherapy with external beam radiotherapy in
localized prostate cancer. Decrease in the number of cells with high
ploidies of chromosomes 7, 8 and 12 at 12 weeks after treatment may
predict clinical effects of radiation therapy, which may explain the
radiation dependency of localized prostate cancer cells.
2
UI - 11748358
AU - Chung WB; Hong SH; Kim JA; Sohn YK; Kim BW; Kim JW
TI -
Hypermethylation of tumor-related genes in genitourinary cancer cell
lines.
SO - J Korean Med Sci 2001 Dec;16(6):756-61
AD - Department of Dental Microbiology, College of Dentistry, Kyungpook
National University, Taegu, Korea. jwkim@knu.ac.kr
Hypermethylation of CpG island is a common mechanism for the
inactivation of tumor-related genes. In the present study, we analyzed
13 genitourinary cancer cell lines for aberrant DNA methylation of 5
tumor-related genes using methylation- specific polymerase chain
reaction (MSP). GSTP1 was methylated in 5 (38.5%), E-cadherin in 1 (8%),
VHL in 1 (8%), and MGMT and hMLH1 in none (0%). Six out of thirteen
genitourinary cancer cell lines had methylation of at least one of five
genes; 5 had one gene methylated, and, 1 had two genes methylated.
Methylation of these 5 genes was not detected in any of the bladder
cancer cell lines. GSTP1 was methylated in all of the 3 prostate cancer
cell lines. We conclude that aberrant hypermethylation may be an
important mechanism for the inactivation of cancer-related genes in
kidney and prostate cancer cell lines.
3
UI - 11813205
AU - Leube B; Drechsler M; Muhlmann K; Schafer R; Schulz WA; Santourlidis S;
TI -
Anastasiadis A; Ackermann R; Visakorpi T; Muller W; Royer-Pokora B
Refined mapping of allele loss at chromosome 10q23-26 in prostate
cancer.
SO - Prostate 2002 Feb 15;50(3):135-44
AD - Institute of Human Genetics, University of Dusseldorf, Dusseldorf,
Germany.
BACKGROUND: Allele loss of at least two segments in 10q, one mapping to
the PTEN gene and one more distal were described in prostate cancer,
with loss more frequent in advanced prostate cancer. METHODS: A 63 cM
region from 10q23 to q26 was studied for allele loss (LOH) in 59
prostate cancer samples using a dense map of microsatellite markers.
RESULTS: LOH of at least one marker in 10q was observed in 13/59 tumors.
LOH increased with grade and stage. Detailed deletion mapping identified
three regions of allele loss. The first region mapped to the site of the
PTEN gene, the second is defined by loss of one marker, D10S1692, in one
tumor, and the third is defined between markers D10S1757 and D10S587,
including DMBT, with a subregion of approximately 1.2 Mb mapping between
markers D10S209 and D10S1679, lost in one tumor. CONCLUSIONS: LOH at the
PTEN gene is frequent but mutations in the remaining allele were not
detected by SSCP-screening. There may be more than two tumor suppressor
(TS) genes mapping more distal of PTEN. The site for these putative TS
genes can now be mapped with a dense set of precisely localized markers
in a larger series of advanced tumors. Copyright 2002 Wiley-Liss, Inc.
4
UI - 11813207
AU - Takahashi S; Suzuki S; Inaguma S; Ikeda Y; Cho YM; Nishiyama N; Fujita
TI -
T; Inoue T; Hioki T; Sugimura Y; Ushijima T; Shirai T
Down-regulation of human X-box binding protein 1 (hXBP-1) expression
correlates with tumor progression in human prostate cancers.
SO - Prostate 2002 Feb 15;50(3):154-61
AD - First Department of Pathology, Nagoya City University Medical School,
Mizuho-Cho, Mizuho-Ku, Nagoya, Japan. sattak@med.nagoya-cu.ac.jp
BACKGROUND: In our previous study, the gene encoding the human X-box
binding protein 1 (hXBP-1) was isolated as a down-regulated gene in
advanced prostate cancers using cDNA-representational difference
analysis (RDA). In the present investigation, we characterized
alterations of hXBP-1 in prostate cancer specimens. METHODS: Expression
patterns of hXBP-1 in a series of human prostate cancers were examined
by Northern blotting, mRNA in situ hybridization or
immunohistochemistry. Loss of heterozygosity (LOH) analysis using
microsatellite markers and gene mutation analysis in the hXBP-1 region
were also performed. RESULTS: Expression of hXBP-1 was localized in
epithelial and adenocarcinoma cells of the prostate. An inverse
correlation between hXBP-1 expression and histological differentiation
was found in a series of prostate cancers without hormonal therapy.
Majority of refractory cancer cases exhibited weak hXBP-1 expression. No
allelic loss or gene mutations were found in the hXBP-1 region and its
open reading frame, respectively, in the prostate cancer examined.
CONCLUSIONS: These results suggest that reduction of hXBP-1 expression
may be a useful marker for prostate adenocarcinoma differentiation and
progression. Copyright 2002 Wiley-Liss, Inc.
5
UI - 11813208
AU - Waltregny D; Alami Y; Clausse N; de Leval J; Castronovo V
TI -
Overexpression of the homeobox gene HOXC8 in human prostate cancer
correlates with loss of tumor differentiation.
SO - Prostate 2002 Feb 15;50(3):162-9
AD - Metastasis Research Laboratory, University Hospital of Liege, Liege,
Belgium. David.Waltregny@ulg.ac.be
BACKGROUND: Homeobox (HOX)-containing proteins have been identified as
regulators controlling the coordinated expression of genes involved in
development and differentiation. Recent data also suggest a possible
involvement of HOX genes in malignant transformation and/or progression.
We have previously shown that HOXC8 expression was selectively turned on
in human cervix cancer cells compared with normal keratinocytes,
suggesting that HOXC8 may be involved in the process leading to the
transformation of cervix keratinocytes [Alami et al.: Biochem Biophys
Res Commun 257:738-745, 1999]. METHODS: RT-PCR and in situ hybridization
experiments were performed to investigate the expression and cell type
localization of HOXC8 transcripts in human prostate cancer cell lines
and tissues. In situ hybridization was performed with the use of an
HOXC8 anti-sense digoxigenin-labeled probe to investigate HOXC8 mRNA
expression in 27 prostate cancer tissue specimens. RESULTS: Out of the
three human prostate cancer cell lines tested, DU-145 and PC3 but not
LNCaP cells expressed detectable amount of HOXC8 transcripts. Results
from in situ hybridization experiments demonstrated that HOXC8 gene was
expressed mainly in malignant epithelial cells. Furthermore, the
staining intensity in epithelial cells was significantly increased in
high Gleason score carcinomas (scores 7-9, n = 12; labeling intensity 2
+ to 3 +) compared with the one observed in low and intermediate Gleason
score tumors (scores 3-6, n = 15; labeling intensity 0 and 1 +) (ANOVA
test, P < 0.0001). CONCLUSIONS: Our data showing that HOXC8
overexpression is associated with the loss of tumor differentiation in
human prostate cancer suggests that HOXC8 may play a role in the
acquisition of the invasive and metastatic phenotype of this malignancy.
Copyright 2002 Wiley-Liss, Inc.
6
UI - 11813210
AU - July LV; Akbari M; Zellweger T; Jones EC; Goldenberg SL; Gleave ME
TI -
Clusterin expression is significantly enhanced in prostate cancer cells
following androgen withdrawal therapy.
SO - Prostate 2002 Feb 15;50(3):179-88
AD - The Prostate Centre, Vancouver General Hospital, University of British
Columbia, Vancouver, British Columbia, Canada.
INTRODUCTION AND OBJECTIVES: Progression of prostate cancer to androgen
independence (AI) results in part from the upregulation of
anti-apoptotic genes following androgen withdrawal, and
androgen-independent disease remains the primary obstacle to improved
survival. Testosterone-repressed prostate message-2 (TRPM-2) encodes the
anti-apoptotic protein clusterin, which is upregulated in response to
cellular compromise as observed in normal and malignant tissues
undergoing apoptosis. Systemic administration of antisense clusterin
oligonucleotides in prostate cancer xenograft models delays progression
to AI and enhances chemosensitivity. The objective of this study was to
define changes in clusterin expression following neoadjuvant hormone
therapy (NHT) in prostate cancer patients. MATERIALS AND METHODS:
Archival radical prostatectomy (RP) specimens were obtained for 128
patients who received either no NHT or treatment for 2-8 weeks, 3
months, or 8 months. Paired needle biopsy specimens were acquired for 30
patients and all tissues were subjected to clusterin
immunohistochemistry. Western blot analysis was performed on frozen
tissue from 5 untreated and 5 treated patients. RESULTS: Clusterin
expression in malignant prostatic tissue was significantly greater in
patients who underwent preoperative NHT (P < 0.001). Needle biopsies
obtained prior to NHT consistently demonstrated lower staining intensity
than corresponding RP specimens (P < 0.001). Western blot analysis
confirmed clusterin levels increased 17-fold beginning within 4 weeks
after androgen withdrawal. CONCLUSIONS: Upregulation of clusterin levels
following androgen ablation therapy may represent an adaptive cell
survival response following apoptotic signals like androgen withdrawal.
These findings support clusterin as a valid therapeutic target in
strategies employing novel multimodality therapy for advanced prostate
cancer. Copyright 2002 Wiley-Liss, Inc.
7
UI - 11799394
AU - Carpten J; Nupponen N; Isaacs S; Sood R; Robbins C; Xu J; Faruque M;
TI -
Moses T; Ewing C; Gillanders E; Hu P; Bujnovszky P; Makalowska I;
Baffoe-Bonnie A; Faith D; Smith J; Stephan D; Wiley K; Brownstein M;
Gildea D; Kelly B; Jenkins R; Hostetter G; Matikainen M; Schleutker J;
Klinger K; Connors T; Xiang Y; Wang Z; De Marzo A; Papadopoulos N;
Kallioniemi OP; Burk R; Meyers D; Gronberg H; Meltzer P; Silverman R;
Bailey-Wilson J; Walsh P; Isaacs W; Trent J
Germline mutations in the ribonuclease L gene in families showing
linkage with HPC1.
SO - Nat Genet 2002 Feb;30(2):181-4
AD - Cancer Genetics Branch, National Human Genome Research Institute, NIH,
Bethesda, Maryland 20892, USA.
Although prostate cancer is the most common non-cutaneous malignancy
diagnosed in men in the United States, little is known about inherited
factors that influence its genetic predisposition. Here we report that
germline mutations in the gene encoding
2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in
prostate cancer families that show linkage to the HPC1 (hereditary
prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a
positional cloning/candidate gene method, and show that a nonsense
mutation and a mutation in an initiation codon of RNASEL segregate
independently in two HPC1-linked families. Inactive RNASEL alleles are
present at a low frequency in the general population. RNASEL regulates
cell proliferation and apoptosis through the interferon-regulated 2-5A
pathway and has been suggested to be a candidate tumor suppressor gene.
We found that microdissected tumors with a germline mutation showed loss
of heterozygosity and loss of RNase L protein, and that RNASEL activity
was reduced in lymphoblasts from heterozyogous individuals compared with
family members who were homozygous with respect to the wildtype allele.
Thus, germline mutations in RNASEL may be of diagnostic value, and the
2-5A pathway might provide opportunities for developing therapies for
those with prostate cancer.
8
UI - 11830513
AU - Takaha N; Hawkins AL; Griffin CA; Isaacs WB; Coffey DS
TI -
High mobility group protein I(Y): a candidate architectural protein for
chromosomal rearrangements in prostate cancer cells.
SO - Cancer Res 2002 Feb 1;62(3):647-51
AD - Department of Urology, The Johns Hopkins University School of Medicine,
Marburg 121, 600 North Wolfe Street, Baltimore, MD 21287, USA.
The extent of chromosomal rearrangements correlates positively with the
level of expression of the nuclear matrix high mobility group (HMG)
proteins HMGI(Y) when tested in three human prostate cancer cell lines
(PC-3 > DU-145 > LNCaP). HMGI(Y), topoisomerase II, and A-T-rich
sequences have been reported to be located at the base of the DNA loop
domains in both the nucleus and chromosome and are juxtapositioned for
chromosomal rearrangement. Transfecting and expressing full-length HMG-I
into the LNCaP cell markedly enhanced the presence and heterogeneity of
unbalanced (nonreciprocal) chromosomal rearrangements but not of
balanced rearrangements. Unbalanced chromosomal rearrangements are
common in solid human tumors.
9
UI - 11830526
AU - Qi H; Fillion C; Labrie Y; Grenier J; Fournier A; Berger L; El-Alfy M;
TI -
Labrie C
AIbZIP, a novel bZIP gene located on chromosome 1q21.3 that is highly
expressed in prostate tumors and of which the expression is up-regulated
by androgens in LNCaP human prostate cancer cells.
SO - Cancer Res 2002 Feb 1;62(3):721-33
AD - Molecular Endocrinology and Oncology Research Center, Centre Hospitalier
Universite Laval Research Center (CHUQ) and Laval University, Quebec G1V
4G2, Canada.
Androgens play an important role in the development and physiology of
the normal prostate as well as in prostate cancer cell proliferation.
Comparison of the mRNA expression profiles of control and R1881-treated
cultures of LNCaP human prostate cancer cells using cDNA subtraction led
to the identification of a novel transcription factor that we named
Androgen-Induced bZIP (AIbZIP) protein. AIbZIP is a 395 aa protein with
homology to cyclic AMP-responsive element binding protein/activating
transcription factor transcription factors. It contains an
NH(2)-terminal activation domain, a central bZIP domain, and a
COOH-terminal transmembrane domain. The AIbZIP gene is localized on
chromosome 1q21.3 and consists of 10 exons. A major 1.7-kb transcript
was detected exclusively in the prostate as well as in breast and
prostate cancer cell lines. Androgens up-regulate AIbZIP mRNA and
protein levels in a dose-dependent manner. The kinetics of AIbZIP mRNA
up-regulation and the results of experiments with cycloheximide suggest
that AIbZIP may be a delayed response gene. Immunoreactive AIbZIP
protein was primarily detected in the cytoplasm of prostatic luminal
epithelial cells. Similarly, full-length AIbZIP-green fluorescent
protein fusion proteins were localized in the cytoplasm of LNCaP cells,
whereas a truncated form of AIbZIP lacking the putative transmembrane
domain was exclusively nuclear. Examination of AIbZIP protein and mRNA
expression in a series of transurethral resection of the prostate and
needle biopsy specimens indicated that AIbZIP is expressed at higher
levels in cancerous prostate cells compared with noncancerous prostate
cells. The highly tissue-specific expression profile, androgen
regulation, chromosomal localization, and expression profile of AIbZIP
in prostate tumors suggest that AIbZIP may play an important role in
prostate cancer and in androgen receptor signaling in prostate cells.
Future studies will confirm a possible relationship between AIbZIP and
prostate cancer.
10
UI - 11830536
AU - Rylova SN; Amalfitano A; Persaud-Sawin DA; Guo WX; Chang J; Jansen PJ;
TI -
Proia AD; Boustany RM
The CLN3 gene is a novel molecular target for cancer drug discovery.
SO - Cancer Res 2002 Feb 1;62(3):801-8
AD - Department of Pediatrics, Duke University Medical Center, Durham, North
Carolina 27710, USA.
Juvenile Batten disease is a neurodegenerative disease caused by
accelerated apoptotic death of photoreceptors and neurons attributable
to defects in the CLN3 gene. CLN3 is antiapoptotic when overexpressed in
NT2 neuronal precursor cells. CLN3 negatively modulates endogenous
ceramide levels in NT2 cells and acts upstream of ceramide generation.
Because defects in regulation of apoptosis are involved in the
development of cancer, we evaluated the expression of CLN3 on both mRNA
and protein levels in a variety of cancer cell lines and solid colon
cancer tissue. We also observed the effect of the blocking of CLN3
protein expression on cancer cell growth, survival, ceramide production,
and apoptosis by using an adenovirus-bearing antisense CLN3 construct.
We show that CLN3 mRNA and protein are overexpressed in glioblastoma
(U-373G and T98g), neuroblastoma (IMR-32 and SK-N-MC), prostate (Du145,
PC-3, and LNCaP), ovarian (SK-OV-3, SW626, and PA-1), breast (BT-20,
BT-549, and BT-474), and colon (SW1116, SW480, and HCT 116) cancer cell
lines but not in pancreatic (CAPAN and As-PC-1) or lung (A-549 and
NCI-H520) cancer cell lines. CLN3 is also up-regulated in mouse melanoma
and breast carcinoma cancer cell lines. We found CLN3 expression is
22-330% higher than in corresponding normal colon control tissue in 8 of
10 solid colon tumors. An adenovirus-expressing antisense CLN3
(Ad-AS-CLN3) blocks CLN3 protein expression in DU-145, BT-20, SW1116,
and T98g cancer cell lines as seen by Western blot. Blocking of CLN3
expression using Ad-AS-CLN3 inhibits growth and viability of cancer
cells. It also causes elevation in endogenous ceramide production
through de novo ceramide synthesis and results in increased apoptosis as
shown by propidium iodide and JC-1 staining. This suggests that
Ad-AS-CLN3 may be an option for therapy in some cancers. More
importantly these results suggest that CLN3 is a novel molecular target
for cancer drug discovery.
11
UI - 11708878
AU - Rubinchik S; Wang D; Yu H; Fan F; Luo M; Norris JS; Dong JY
TI -
A complex adenovirus vector that delivers FASL-GFP with combined
prostate-specific and tetracycline-regulated expression.
SO - Mol Ther 2001 Nov;4(5):416-26
AD - Department of Microbiology and Immunology, Medical University of South
Carolina, Charlestown, SC 29403, USA
Cell-type-restricted transgene expression delivered by adenovirus
vectors is highly desirable for gene therapy of cancer, as it can limit
cytotoxic gene expression to tumor cells. However, many tumor- and
tissue-specific promoters are weaker than the constitutively active
promoters and are thus less effective. To combine cell-type specificity
with high-level regulated transgene expression, we have developed a
complex adenoviral vector. We have placed the tetracycline
transactivator gene under the control of a prostate-specific ARR2PB
promoter, and a mouse Tnfsf6 (encoding FASL)-GFP fusion gene under the
control of the tetracycline responsive promoter. We have incorporated
both expression cassettes into a single construct. We show that FASL-GFP
expression from this vector is essentially restricted to prostate cancer
cells, in which it can be regulated by doxycycline. Higher levels of
prostate-specific FASL-GFP expression were generated by this approach
than by driving the FASL-GFP expression directly with ARR2PB. More
FASL-GFP expression correlated with greater induction of apoptosis in
prostate cancer LNCaP cells. Mouse studies confirmed that systemic
delivery of both the prostate-specific and the
prostate-specific/tet-regulated vectors was well tolerated at doses that
were lethal for FASL-GFP vector with CMV promoter. This strategy should
be able to improve the safety and efficacy of cancer gene therapy using
other cytotoxic genes as well.
12
UI - 11857301
AU - Velasco A; Hewitt SM; Albert PS; Hossein M; Rosenberg H; Martinez C;
TI -
Sagalowsky AI; McConnell JD; Marston W; Leach FS
Differential expression of the mismatch repair gene hMSH2 in malignant
prostate tissue is associated with cancer recurrence.
SO - Cancer 2002 Feb 1;94(3):690-9
AD - Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland
20892-1501, USA.
BACKGROUND: Mismatch repair (MMR) genes are responsible for coordinated
correction of misincorporated nucleotides formed during DNA replication.
Inactivating mutations in MMR genes have been described in sporadic
cancers and a hereditary cancer predisposition syndrome. Mismatch repair
deficiency causes instability at microsatellites and increased mutation
rates. Although microsatellite instability (MSI) has been described in
high-grade and lymph node positive prostate carcinoma specimens, an
analysis comparing hMSH2 expression, MSI, and outcome in clinically
organ confined prostate carcinoma has not been reported. METHODS:
Immunohistochemical analysis of benign and malignant prostate tissue
from 101 patients was performed using a monoclonal antibody specific for
the hMSH2 protein. Expression was correlated with MSI using dinucleotide
repeat markers and laser-captured microdissected DNA from normal and
tumor cells. hMSH2 protein expression and MSI were assessed with respect
to pathologic stage, Gleason score, and time to detectable serum
prostate specific antigen (PSA) after prostatectomy in patients with
clinically localized prostate carcinoma. RESULTS: In normal glands,
hMSH2 staining was minimal to low and confined to the basal cell layer.
In 32% of benign prostatic hyperplasia cases, hMSH2 staining was
increased in the basal and luminal cell layers whereas 71% of cancer
specimens had uniform moderate to high staining. Microsatellite
instability was detected in 60% of absent to low staining and 26% of
moderate to high staining prostate carcinoma specimens. Differential
staining in benign versus malignant prostate tissues was statistically
significant (P < 0.001) as was the correlation between absent to low
hMSH2 staining and presence of MSI (P = 0.028). Decreased risk for PSA
recurrence after radical prostatectomy correlated with absent to low
hMSH2 staining in malignant prostate tissue but was only marginally
significant (P = 0.05 for 24 month recurrence and P = 0.08 for overall
time to PSA recurrence). CONCLUSIONS: The results of the current study
demonstrate differential hMSH2 expression in benign and malignant
prostate tissue. Moreover, hMSH2 expression is altered in a subset of
clinically localized prostate carcinoma specimens independent of
pathologic stage and Gleason pattern. A statistically significant
correlation between hMSH2 immunohistochemical staining intensity and MSI
also was identified in prostate carcinoma specimens. Furthermore, the
time to cancer recurrence as determined by detectable serum PSA after
prostatectomy was associated with hMSH2 staining intensity. Taken
together, our results suggest that hMSH2 gene expression in prostate
carcinoma may be a useful prognostic marker for outcome in men with
clinically organ confined prostate carcinoma. Copyright 2002 American
Cancer Society. DOI 10.1002/cncr.10247
13
UI - 11838717
AU - Weinrich S; Royal C; Pettaway CA; Dunston G; Faison-Smith L; Priest JH;
TI -
Roberson-Smith P; Frost J; Jenkins J; Brooks KA; Powell I
Interest in genetic prostate cancer susceptibility testing among african
American men.
SO - Cancer Nurs 2002 Feb;25(1):28-34
AD - School of Nursing, University of Louisville, KY 40292, USA.
sally.weinrich@louisville.edu
Six regions for prostate cancer genes have been identified, and it is
anticipated that prostate cancer susceptibility testing will be
available in the future. This correlational study identified predictors
for interest in prostate cancer susceptibility testing among African
American men. Participants were 320 African American men from the
African American Hereditary Prostate Cancer Study and the South Carolina
Prostate Cancer Education and Screening Study participated. Two
questions measured interest in genetic prostate cancer susceptibility
testing and family history of prostate cancer. Chi-square analyses by
family history as well as demographics (age, education, marital status)
were performed. Most of the men (277 [87%]) indicated an interest in
genetic prostate cancer susceptibility testing. Interest in undergoing
testing did not vary by family history, age, or education. Marital
status was the only significant demographic predictor. Men who were
married were significantly more likely to respond with a "yes" to
interest in prostate cancer susceptibility testing than were men who
were not married. The high "yes" response rate and the men's confusion
between the genetic prostate cancer susceptibility testing and prostate
cancer screening highlight the need for public education once prostate
cancer genes are identified and available for public testing.
14
UI - 11848465
AU - Honda T; Gjertsen BT; Spurgers KB; Briones F; Lee SJ; Hobbs ML; Meyn RE;
TI -
Roth JA; Logothetis C; McDonnell TJ
Restoration of bax in prostate cancer suppresses tumor growth and
augments therapeutic cell death induction.
SO - Anticancer Res 2001 Sep-Oct;21(5):3141-6
AD - Department of Molecular Pathology, The University of Texas M. D.
Anderson Cancer Center, Houston 77030, USA.
BACKGROUND: Cancer cells are characterized by multiple genetic defects
which result in altered rates of cell division, cell death and ability
to differentiate. These same molecular alterations may also contribute
to therapeutic resistance. We examined the potential contribution of the
pro-apoptotic gene, bax, to suppressing the growth of prostate cancer
cells. MATERIALS AND METHODS: The bax-deficient DU145 prostate cancer
cell line was transfected with a hemagluttinin-tagged bax (HA-bax)
vector to generate stable expressing bax clones. RESULTS: Ha-bax clones
exhibited a significant reduction in tumor growth compared to vector
control and parental cells when xenografted into nude mice. HA-bax
clones were significantly more sensitive to cell death induction by
cis-diamminedichloroplatinum, etoposide, doxorubicin and gamma-radiation
than vector control cells. Sensitivity to paclitaxel remained unaltered
in the Ha-bax cells. CONCLUSION: These findings suggest that bax may
possess a tumor suppressor function in prostatic glandular epithelial
cells and be an important determinant of sensitivity to therapeutic cell
death induction.
15
UI - 11865006
AU - Oxley JD; Winkler MH; Gillatt DA; Peat DS
TI -
Her-2/neu oncogene amplification in clinically localised prostate
cancer.
SO - J Clin Pathol 2002 Feb;55(2):118-20
AD - Department of Cellular Pathology, Southmead Hospital, Westbury on Trym,
Bristol BS10 5NB, UK. jon@jon-oxley.freeserve.co.uk
AIM: To examine the incidence of Her-2/neu oncogene amplification in
clinically localised prostate cancer using in situ hybridisation.
METHODS: One hundred and seventeen patients, who had undergone radical
prostatectomy, were identified and in situ hybridisation was performed
on formalin fixed, paraffin wax embedded tissue using the Quantum
Appligene probe for Her-2/neu. The enzyme peroxidase was used to detect
the probe because this enabled a permanent record to be kept. Tumours in
which there were five or more signals in each nucleus in > 20% of the
tumour cells were considered to have a significantly increased copy
number. A serial section from these tumours was then hybridised with the
chromosome 17 alpha satellite probe. The ratio of the percentage of
cells showing an increase in Her-2/neu copy number to the number showing
polysomy for chromosome 17 was calculated. A ratio above 2 was
considered amplified. RESULTS: Biochemical recurrence occurred in 50
(43%) patients and 24 (21%) had clinical recurrence. In situ
hybridisation for Her-2/neu was accessible in 114 (97%) patients. A
significant increase in copy number was present in two patients (1.75
%), but chromosome 17 hybridisation showed that the increase was the
result of polysomy rather than true amplification. Both these patients
had a Gleason score of 7 and stage T3; they also had recurrent clinical
disease with distal metastasis within two and 19 months. CONCLUSIONS:
Increased Her-2/neu oncogene copy number appears to be rare in
clinically localised prostatic adenocarcinoma and is related to
chromosome 17 polysomy rather than true amplification. As a result, it
would not be a useful biomarker for identifying those patients who will
have recurrences after radical prostatectomy.
16
UI - 11176509
AU - Wullich B; Verelst S; Rohde V; Moll V; Lensch R; Retz M; Loch T; Zwergel
TI -
T; Seitz G; Forster S; Stockle M
High frequency microsatellite instability in mucinous adenocarcinoma of
the prostate.
SO - J Urol 2001 Mar;165(3):912-3
AD - Clinic of Urology and Pediatric Urology, University of Saar,
Homburg/Saar, Institute of Pathology, Clinic of Bamberg, Bamberg,
Germany.
17
UI - 11825111
AU - Al-Maghrabi J; Vorobyova L; Toi A; Chapman W; Zielenska M; Squire JA
TI -
Identification of numerical chromosomal changes detected by interphase
fluorescence in situ hybridization in high-grade prostate
intraepithelial neoplasia as a predictor of carcinoma.
SO - Arch Pathol Lab Med 2002 Feb;126(2):165-9
AD - Ontario Cancer Institute, Princess Margaret Hospital, 610 University
Ave, Toronto, Ontario, Canada M5G 2M9.
CONTEXT: High-grade prostate intraepithelial neoplasia (HPIN) is the
most likely precursor of prostate cancer. The condition of many patients
with a diagnosis of HPIN in prostate needle core biopsy could, if left
untreated, progress to invasive cancer. Currently there is no available
clinical, immunohistochemical, or morphologic criteria that are
predictive of this progression. OBJECTIVE: To determine whether
chromosomal instability in these precursor lesions could increase their
predictive value for cancer detection. DESIGN: Dual-color interphase
fluorescence in situ hybridization analysis was performed on archived
prostate needle core biopsies from 54 patients with initial diagnosis of
isolated HPIN and follow-up of 3 years or more. We used commercially
available centromere probes for chromosomes 4, 7, 8, and 10. We had
interpretable results in 44 patients as follows: (1) group A: 24 HPIN
patients with persistent HPIN and/or benign lesions in the follow-up
biopsies, and (2) group B: 20 HPIN patients with progression to prostate
carcinoma. RESULTS: Twenty-five percent of the patients in group B
displayed numeric chromosomal aberrations. Only 8.3% of the patients
from group A had chromosomal abnormalities (P =.1). The observed overall
chromosomal changes in HPIN were higher than those in normal or
hyperplastic epithelium, with a statistically significant difference (P
<.05). All aberrations were detected in the form of chromosomal gain.
Overall, the commonest aberration was gain of chromosome 8, followed by
gains of chromosomes 7 and 10. CONCLUSION: These results indicated that
although no single numeric chromosomal abnormality could be assigned as
a predictor of HPIN progression to carcinoma, the overall level of
numeric chromosomal abnormalities shows a trend of elevation in HPIN
patients whose condition subsequently progressed to carcinoma.
18
UI - 11673464
AU - Miyamoto H; Rahman M; Takatera H; Kang HY; Yeh S; Chang HC; Nishimura K;
TI -
Fujimoto N; Chang C
A dominant-negative mutant of androgen receptor coregulator ARA54
inhibits androgen receptor-mediated prostate cancer growth.
SO - J Biol Chem 2002 Feb 15;277(7):4609-17
AD - George Whipple Laboratory for Cancer Research, Department of Pathology,
University of Rochester Medical Center, Rochester, New York 14642, USA.
The ligand-bound androgen receptor (AR) regulates target genes via a
mechanism involving coregulators such as androgen receptor-associated 54
(ARA54). We investigated whether the interruption of the AR coregulator
function could lead to down-regulation of AR activity. Using in vitro
mutagenesis and a yeast two-hybrid screening assay, we have isolated a
mutant ARA54 (mt-ARA54) carrying a point mutation at amino acid 472
changing a glutamic acid to lysine, which acts as a dominant-negative
inhibitor of AR transactivation. In transient transfection assays of
prostate cancer cell lines, the mt-ARA54 suppressed endogenous mutated
AR-mediated and exogenous wild-type AR-mediated transactivation in LNCaP
and PC-3 cells, respectively. In DU145 cells, the mt-ARA54 suppressed
exogenous ARA54 but not other coregulators, such as ARA55-enhanced or
SRC-1-enhanced AR transactivation. In the LNCaP cells stably transfected
with the plasmids encoding the mt-ARA54 under the doxycycline inducible
system, the overexpression of the mt-ARA54 inhibited cell growth and
endogenous expression of prostate-specific antigen. Mammalian two-hybrid
assays further demonstrated that the mt-ARA54 can disrupt the
interaction between wild-type ARA54 molecules, suggesting that ARA54
dimerization or oligomerization may play an essential role in the
enhancement of AR transactivation. Together, our results demonstrate
that a dominant-negative AR coregulator can suppress AR transactivation
and cell proliferation in prostate cancer cells. Further studies may
provide a new therapeutic approach for blocking AR-mediated prostate
cancer growth.
19
UI - 11854382
AU - Dunn FB
TI -
Mutation analysis suggests role for ribonuclease L gene in prostate
cancer.
SO - J Natl Cancer Inst 2002 Feb 20;94(4):244-5
20
UI - 11713582
AU - Wu SQ; Hafez GR; Zhang J; Newton M; Chen A; Lange J; Wilding G
TI -
Identification of the prostate cancer micro-foci with chromosome 8p
deletion at the tumor interface area by histopathological-FISH parallel
examination.
SO - Int J Oncol 2001 Dec;19(6):1143-7
AD - Division of Medical Genetics, Childrens Hospital Los Angeles, Keck
School of Medicine, University of Southern California, Los Angeles, CA
90027, USA. swu@chla.usc.edu
We used a histopathological-fluorescence in situ hybridization
(histo-FISH) parallel examination technique to identify the micro-foci
of prostate cancer with chromosome 8p deletion at the interface area
adjacent to the tumor. The archival paraffin embedded prostate tissue
sections from 27 prostate cancer patients were evaluated. Seventy-eight
percent of the patients showed chromosome 8p deletion in the tumor
sections. Eight of the 27 patients (30%) had been found positive for
tumor micro-foci with chromosome 8p deletion at the tumor interface
area. There is a strong trend for patients with late stage tumors to
have positive findings for tumor micro-foci at the interface area
(p<0.002). Our data suggests that the formation of tumor micro-foci with
chromosome 8p deletion and ploidy change at the interface area is a
significant development in the advanced prostate cancer, and
identification of these micro-foci may serve as a prognostic parameter
in the clinical assessment of prostate cancer patients.
21
UI - 11713598
AU - Verdorfer I; Hobisch A; Culig Z; Hittmair A; Bartsch G; Erdel M; Duba
TI -
HC; Utermann G
Combined study of prostatic carcinoma by classical cytogenetic analysis
and comparative genomic hybridization.
SO - Int J Oncol 2001 Dec;19(6):1263-70
AD - Institut fur Medizinische Biologie und Humangenetik der Universitat
Innsbruck, A-6020 Innsbruck, Austria.
Conventional cytogenetic analysis of prostatic carcinoma (PC) is
characterized by inefficient growth of tumor cells during in vitro
culture, leading to a lack of aberrant karyotypes in many of
investigated tumors. In this study we have combined a modified
short-term tissue culture method for conventional banding analysis and
comparative genomic hybridization (CGH) to examine genetic changes in
PC, and to evaluate the effect of the in vitro culture on chromosomal
changes by comparing results of the two methods. Cytogenetic analysis
was performed on 34 PCs using both, conventional and molecular methods.
Tumor tissues were obtained predominantly from untreated primary tumors
from 48 patients. For karyotyping all tumor samples were short-term
cultured using a feeder layer technique. Additionally DNA from
uncultured tumor material from 17 of those patients was isolated and
screened for copy number changes using CGH. Conventional banding
analysis: clonal aberrations were detected in 65% of the tumor samples.
Most of the chromosomal findings were numerical changes, including loss
of chromosomes Y (32%), 18, 19 and 21 (each 12%). Less frequent, trisomy
of chromosome 7 and monosomy of chromosomes 9, 12 and 22 (each 9%) was
found. Additionally an inversion of chromosome 9p and a deletion at
chromosome 7q was found in two cases. In 35% no clonal aberrations could
be detected. CGH: DNA copy number changes were detected in 65% of the
analyzed tumors. Predominantly losses of DNA sequences were found. The
most common losses were found at chromosome regions 13q21q33 (29%),
6q11q23 (24%), 16q, and 18 (each 18%), and the most common gains at 19
(18%). In six tumors no copy number changes were found. Both methods
showed a similar aneuploidy rate, suggesting that the feeder layer
technique is quite a suitable method for in vitro culture of PC cells.
However, the two techniques produced substantially differing results for
most of the tumor samples, and in some cases the discrepancies are quite
striking. Therefore eventual culture effects need to be taken into
account when comparing results from conventional cytogenetics and CGH.
Some contrary findings from the two methods are discussed.
22
UI - 11783090
AU - Li C; Dong J; Guan W
TI -
[CAG microsatellite polymorphisms of androgen receptor gene and the
stage and grade of prostate cancer]
SO - Zhonghua Zhong Liu Za Zhi 2001 May;23(3):217-9
AD - Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking
Union Medical College, Beijing 100021, China.
OBJECTIVE: To explore the relationship between the CAG microsatellite in
androgen receptor (AR) gene and the stage and grade of prostate
cancer(PC). METHODS: The number of CAG repeats in exon 1 of the AR gene
was measured in 37 PC tissues by PCR-SSCP analysis, and its association
with stages and grades of PC determined. RESULTS: The average number of
CAG repeats of AR gene differed significantly between PC in stage B
(25.04 +/- 1.88) and in stage C-D (24.14 +/- 2.64) (P = 0.002). The
frequency of short CAG(< 22) was 13.0% (3/23) in stage B and 28.6%(4/14)
in stage C-D, while that of long CAG(> or = 22) was 87.0% (20/23) and
71.4% (10/14) (P = 0.029), respectively. The average number of CAG
repeats increased with the decrease in tumor cell differentiation. The
frequency of short CAG repeats dropped with the increase in tumor cell
differentiation while the opposite was true for that of long CAG
repeats. CONCLUSION: The number of CAG repeats in AR gene may be one of
the factors determining the biologic characteristics PC. Short CAG
repeats may signify aggressiveness of PC.
23
UI - 11856117
AU - Wolter H; Gottfried HW; Mattfeldt T
TI -
Genetic changes in stage pT2N0 prostate cancer studied by comparative
genomic hybridization.
SO - BJU Int 2002 Feb;89(3):310-6
AD - Department of Pathology, University of Ulm, Ulm, Germany.
OBJECTIVE: To identify chromosomal regions important for progression in
clinically organ-confined prostate cancer, as the genetic changes
underlying the development and progression of prostate cancer are poorly
understood. MATERIALS AND METHODS: Comparative genomic hybridization
(CGH) was used to search for DNA sequence copy-number changes in a
series of 50 primary organ-confined prostate adenocarcinomas (pT2N0)
removed by radical prostatectomy. RESULTS: CGH analysis indicated that
23 (46%) of the primary prostate adenocarcinomas showed chromosome
alterations. The percentage of tumours with losses (38%) was higher than
with gains (28%). Losses of 13q (24%), 8p (18%), 6q (10%), 16q (8%), 18q
(6%) and 5q (6%) and gains of 17q (12%), 20q (12%), 9q (10%), 17p (8%)
and 8q (6%) were the most frequent alterations. Amplifications were
found at 8q24-qter. Minimal overlapping regions of loss, indicative of
the presence of tumour-suppressor genes, were mapped to 13q21.1-q21.3
and 8p21.2, and minimal overlapping regions of gain, indicative of the
presence of oncogenes, were found at 9q34.4-qter, 17q25-qter and
20q13.3-qter. There was a significant association between Gleason score
and losses and gains (P = 0.003), and an association between chromosomal
imbalance and high histological grade (P = 0.008). CONCLUSION: These
results suggest that losses or gains of DNA in these regions are
important for prostate cancer progression, and document the spectrum of
chromosomal alterations in stage pT2N0 of clinically organ-confined
prostate cancer.
24
UI - 11880477
AU - Sasaki M; Tanaka Y; Perinchery G; Dharia A; Kotcherguina I; Fujimoto S;
TI -
Dahiya R
Methylation and inactivation of estrogen, progesterone, and androgen
receptors in prostate cancer.
SO - J Natl Cancer Inst 2002 Mar 6;94(5):384-90
AD - Department of Urology, University of California, San Francisco 94121,
USA.
BACKGROUND: Prostate cancer development is initially steroid hormone
dependent. Estrogen receptors (ERs), androgen receptors (ARs), and
progesterone receptors (PRs) have been identified in normal and
cancerous prostate tissues. We investigated whether the promoter regions
of these steroid receptor genes are methylated and inactivated in
prostate cancer cells and tissues. METHODS: The expression and promoter
methylation status of three ERalpha isoforms (ERalpha-A, ERalpha-B, and
ERalpha-C), ERbeta, two PR isoforms (PR-A and PR-B), and AR were
investigated in five prostate cancer cell lines (ND1, DU145, PC3, LNCaP,
and DUPro) and in pairs of normal and cancerous prostate tissues from 38
patients with prostate cancer. Methylation-specific polymerase chain
reaction, reverse transcription--polymerase chain reaction, and 5' rapid
amplification of complementary DNA ends were used. All statistical tests
were two-sided. RESULTS: ERalpha-C was expressed in all cell lines, but
ERalpha-A and ERalpha-B were not expressed in any cell line. ERalpha-A
and ERalpha-B promoters were methylated, but ERalpha-C was unmethylated.
Promoters for ERbeta, AR, PR-A, and PR-B were methylated and thus
inactivated in some cell lines but not in others. Treating cells with
the demethylating reagent 5-aza-2'-deoxycytidine restored expression of
all steroid receptor genes with previously methylated promoters. All 38
pairs of cancer and normal tissues had unmethylated ERalpha-C promoters.
Thirty-six (95%) of 38 cancers had methylated ERalpha-A, 35 (92%) of 38
cancers had methylated ERalpha-B, but all normal tissues had
unmethylated ERalpha-A and ERalpha-B (both P<.001). ERbeta was
methylated in 30 (79%) of 38 cancers but unmethylated in all normal
tissues. AR was methylated in three (8%) of 38 cancers but unmethylated
in all normal tissues. PR-A and PR-B were unmethylated in all tissues.
CONCLUSION: Certain steroid receptor genes appear to be inactivated by
CpG methylation in prostate cancer tissue and cell lines.
25
UI - 11737226
AU - Finnstrom N; Bjelfman C; Soderstrom TG; Smith G; Egevad L; Norlen BJ;
TI -
Wolf CR; Rane A
Detection of cytochrome P450 mRNA transcripts in prostate samples by
RT-PCR.
SO - Eur J Clin Invest 2001 Oct;31(10):880-6
AD - Department of Medical Laboratory Sciences and Technology, Clinical
Pharmacology, Karolinska Institutet at Huddinge University Hospital,
S-141 86 Stockholm, Sweden. niklas.finnstrom@labtek.ki.se
BACKGROUND: The expression of cytochrome P450 (CYP)-dependent
mono-oxygenases in the prostate is important, as it will determine the
rate of activation of potential carcinogens as well as the metabolism of
hormones with implications in diseases of the prostate. In addition, the
levels of cytochromes P450 in prostatic tumours may well be determinants
of the outcome of therapy involving P450 substrates such as
anti-androgens. METHODS: The gene expression of 12 different CYP genes
was measured by reverse transcription-polymerase chain reaction (RT-PCR)
in a total of 28 human prostatic tumour and nontumour samples. RESULTS:
Intriguingly, a large number of CYP mRNAs were detected in the prostate
samples, including CYP1A2, -1B1, -2C19, -2D6, -3A4, -3A5, -3A7 and -4B1.
CYP1B1 was consistently expressed and CYP3A5 and CYP4B1 were expressed
in a majority of the samples tested. CONCLUSIONS: These data demonstrate
a wide range of CYP genes being expressed in the prostate. The relative
importance of these enzymes in the pathogenesis and treatment of
prostatic disease remains an important theme for further study.
26
UI - 11870798
AU - Jongsma J; Oomen MH; Noordzij MA; Van Weerden WM; Martens GJ; van der
TI -
Kwast TH; Schroder FH; van Steenbrugge GJ
Different profiles of neuroendocrine cell differentiation evolve in the
PC-310 human prostate cancer model during long-term androgen
deprivation.
SO - Prostate 2002 Mar 1;50(4):203-15
AD - Department of Experimental Urology, Josephine Nefkens Institute, Erasmus
University, Rotterdam, Netherlands. jongsma@nki.nl
BACKGROUND: Neuroendocrine (NE) cells are androgen-independent cells and
secrete growth-modulating peptide hormones via a regulated secretory
pathway (RSP). We studied NE differentiation after long-term androgen
withdrawal in the androgen-dependent human prostate cancer xenograft
PC-310. METHODS: Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14,
21, 47, 84, and 154 days after castration. The half-life of the PC-310
tumor was 10 days, with a stable residual tumor volume of 30--40% after
21 days and longer periods of androgen deprivation. RESULTS:
Proliferative activity and prostate-specific antigen serum levels
decreased to zero after castration, whereas cell-cycle arrest was
manifested by increased p27(kip1) expression. A temporary downregulation
of androgen receptor (AR) expression was noted after androgen
deprivation. The expression of chromogranin A, secretogranin III, and
secretogranin V (7B2) increased 5 days after castration and later.
Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating
monooxygenase as well as vascular endothelial growth factor were
expressed from 7 days after castration on. Finally, such growth factors
as gastrin-releasing peptide and serotonin were expressed in a small
part of the NE cells 21 days after castration, but strong expression was
induced late during androgen deprivation, that is, 84 and 154 days after
castration, respectively. CONCLUSIONS: Androgen deprivation of the
NE-differentiated PC-310 model induced the formation of
NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The
NE-differentiated cells actively produced growth factors via an RSP that
may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor
cells were shown to remain androgen sensitive even after long-term
androgen deprivation. In the PC-310 xenograft, time-dependent NE
differentiation and subsequent maturation were induced after androgen
depletion. The androgen-dependent PC-310 xenograft model constitutes an
excellent model for studying the role of NE cells in the progression of
clinical prostate cancer. Copyrig
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