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Abramson Cancer CenterNCI CANCERLIT® Search: Breast Cancer, Hereditary - October 2001
National Cancer Institute®
Last Modified: November 21, 2001
Table of Contents
1
UI - 21274388
AU - Nagasawa H; Kusakawa S
TI -
Two inbred strains of mice with high and low mammary tumor potentials
established from the same basal stock of Swiss albino (SHN and SLN):
history of mammary tumorigenesis and reproduction after the 30th
generation of full-sib mating.
SO - Exp Anim 2001 Apr;50(2):167-71
AD - Experimental Animal Research Laboratory, Meiji University, Tama-ku,
Kawasaki 214-8571, Japan.
We established SHN and SLN strains of mice with a high and a low mammary
tumor potentials from the same basal stock of Swiss albino. The
selection history of females (mothers) for subsequent generations,
mammary tumorigenesis and reproduction up to recent generations are
presented and compared with the results up to F30 published in 1979. The
changes with generation of each parameter varied in both strains except
the conditions of female (mother) selection for subsequent generations,
which were generally constant. However, the fluctuations in parameters
up to F30 became generally smaller with advancing generations. Based on
the fluctuations from generation to generation of mammary tumorigenic
and reproductive parameters, an interdependency between mammary tumor
potential and reproductivity is suggested in SLN, but less so in SHN.
The pup growth rate was increased and associated with selection for
mammary tumorigenesis in SHN; this parameter is usually used as an
indicator of mother lactational performance in mice. The significance of
selection for mammary tumor potential in association with reproductivity
was further discussed.
2
UI - 21283527
AU - Liehr JG
TI -
Genotoxicity of the steroidal oestrogens oestrone and oestradiol:
possible mechanism of uterine and mammary cancer development.
SO - Hum Reprod Update 2001 May-Jun;7(3):273-81
AD - Stehlin Foundation for Cancer Research at Christus St Joseph Hospital,
Houston, Texas 77003, USA. jliehr@stehlin.org
Oestrogens, including the natural hormones oestrone and oestradiol,
induce various tumours in laboratory animals and have been recognized to
be carcinogens in humans, raising the risk for breast and uterine
cancer. As part of the search for the mechanism of hormone-induced
carcinogenesis, various types of DNA damage have been detected which
have been induced by oestrogens in cell-free systems, in cells in
culture, or in vivo. Nevertheless, oestrogens have been postulated to
act only as promoters of mammary carcinogenesis by receptor-mediated
growth stimulation without consideration of their genotoxicity because
these hormones failed to induce mutations in commonly used assays. More
recently, oestradiol-induced numerical chromosomal changes (aneuploidy)
and structural chromosomal aberrations have been detected in cells in
culture and in hamster kidney, a target of oestrogen-induced cancer. In
this animal model, oestradiol generates c-myc gene amplification and
microsatellite instability. Mutations of the hprt gene have been induced
by oestradiol in V79 cells and by catecholoestrogen metabolites in
Syrian hamster embryo cells. Sequencing of this gene isolated from V79
mutant clones revealed point mutations and deletions. It is concluded
that oestradiol plays a dual role as mutagen/carcinogen and as
growth-stimulating hormone in the induction of tumours.
3
UI - 21355685
AU - Tonoki H
TI -
[Cancer, breast, familial]
SO - Ryoikibetsu Shokogun Shirizu 2001;(33):316-7
AD - Chitose Municipal Hospital.
4
UI - 21347324
AU - Chappuis PO; Hamel N; Paradis AJ; Deschenes J; Robidoux A; Potvin C;
TI -
Cantin J; Tonin P; Ghadirian P; Foulkes WD
Prevalence of founder BRCA1 and BRCA2 mutations in unselected French
Canadian women with breast cancer.
SO - Clin Genet 2001 Jun;59(6):418-23
AD - McGill University Health Centre Research Institute, McGill University,
Montreal, Quebec, Canada.
The frequency of BRCA1 and BRCA2 mutations in women with breast cancer
varies according to the age at diagnosis, family history of cancer, and
ethnicity/country of origin. We set out to estimate the frequency of
seven previously described founder mutations in BRCA1 and BRCA2 in all
eligible French Canadian women diagnosed with invasive breast cancer at
one Montreal hospital over a 20-month period. One hundred and ninety-two
patients were eligible and 127 (66.2%) provided blood for genetic
testing. We identified 4 women who carried a founder mutation (3.1%, 95%
confidence interval 0.9-7.9%) in this population. Interestingly, all the
mutations were in BRCA2. The mean age at diagnosis for mutation carriers
was 51.2 years (range 49.1-53.5). Two of these 4 cases were lobular
invasive carcinomas and 2 were ductal carcinomas, histological grade 1
or 2. Despite a small tumor size (< or =20 mm), axillary nodal
involvement was present in 3 women. Estrogen receptors were strongly
expressed in all cases. Two of the 4 cases reported a strong family
history of breast cancer, but a family history of site-specific breast
cancer was a relatively poor indicator of the presence of BRCA2
mutations. The absence of BRCA1 mutations may be a result of chance, but
may also reflect different geographical origins of the most common BRCA1
mutations within the French Canadian population.
5
UI - 21367957
AU - Matsumoto Y; Takano H; Kunishio K; Nagao S; Fojo T
TI -
Expression of drug resistance genes in VP-16 and mAMSA-selected human
carcinoma cells.
SO - Jpn J Cancer Res 2001 Jul;92(7):778-84
AD - Department of Neurological Surgery, Kagawa Medical University, Miki-cho,
Kita-gun, Kagawa 761-0793, Japan. mizaya@kms.ac.jp
The cell lines described in the present study were isolated as part of
an effort to understand resistance to topoisomerase (topo) II
inhibitors. To that end, 50 sublines were isolated from four human
breast cancer cell lines, i.e., MCF-7, T47D, MDA-MB-231, and ZR-75B. As
an initial step, a concentration that would be lethal to the majority of
cells (IC99) was selected for both VP-16 and mAMSA, for each cell line.
The identification of an increasing number of putative drug
resistance-related proteins provided the opportunity to examine
expression of the corresponding genes in the selected cell lines.
Northern blot analysis revealed different responses to the selecting
agents in the different cell lines. Previous studies examining
expression of multidrug resistance (MDR)-1 in resistant cell lines had
found undetectable levels in all cells. In the ZR-75B sublines,
increased expression of MDR-associated protein (MRP) and canalicular
multispecific organic anion transporter (cMOAT) was observed, and when
the relative levels of overexpression were compared, a high correlation
was found. In contrast, increased expression of MRP was observed in some
of the MDA-MB-231 sublines, without a concomitant increase in cMOAT
expression. Finally, in both T47D and MCF-7 sublines, increased
expression of cMOAT or MRP was observed infrequently, and where it
occurred, was of a much smaller magnitude. In the analysis of expression
of MRP, the highest levels were found in the ZR-75B and MDA-MB-231
sublines, with lower levels in the MCF-7 and T47D clones. Similarly,
differences in the expression of topo IIalpha were observed among the
sublines. Although the differences in expression appear to depend on the
parental cell line from which the resistant sublines were derived, a
strong correlation was observed between the expression of MRP and the
levels of topo IIalpha. Cell lines with low levels of MRP had lower
levels of topo IIalpha, while those with high levels of MRP maintained
higher levels of topo IIalpha. While a reduced topo IIalpha level was
common, there did not appear to be a compensating increase in the
expression of topo IIbeta or topo I or casein kinase (CK) IIalpha in any
of the cell lines. While the possibility that such compensation could
occur has been discussed and even reported in some cell lines, such an
adaptation was not observed in the present study, suggesting that it is
not common.
6
UI - 21385662
AU - Teixeira MR; Tsarouha H; Kraggerud SM; Pandis N; Dimitriadis E; Andersen
TI -
JA; Lothe RA; Heim S
Evaluation of breast cancer polyclonality by combined chromosome banding
and comparative genomic hybridization analysis.
SO - Neoplasia 2001 May-Jun;3(3):204-14
AD - Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
mteixeir@ipoporto.min-saude.pt
Cytogenetically unrelated clones have been detected by chromosome
banding analysis in many breast carcinomas. Because these karyotypic
studies were performed on short-term cultured samples, it may be argued
that in vitro selection occurred or that small clones may have arisen
during culturing. To address this issue, we analyzed 37 breast
carcinomas by G-banding and comparative genomic hybridization (CGH), a
fluorescent in situ hybridization--based screening technique that does
not require culturing or tumor metaphases. All but two of the 37
karyotypically abnormal cases presented copy number changes by CGH. The
picture of genomic alterations revealed by the two techniques overlapped
only partly. Sometimes the CGH analysis revealed genomic imbalances that
belonged to cell populations not picked up by the cytogenetic analysis
and in other cases, especially when the karyotypes had many markers and
chromosomes with additional material of unknown origin, CGH gave a more
reliable overall picture of the copy number gains and losses. However,
besides sometimes revealing cell populations with balanced chromosome
aberrations or unbalanced changes that nevertheless remained undetected
by CGH, G-banding analysis was essential to understand how the genomic
imbalances arose in the many cases in which both techniques detected the
same clonal abnormalities. Furthermore, because CGH pictures only
imbalances present in a significant proportion of the test sample, the
very detection by this technique of imbalances belonging to apparently
small, cytogenetically unrelated clones of cells proves that these
clones must have been present in vivo. This constitutes compelling
evidence that the cytogenetic polyclonality observed after short-term
culturing of breast carcinomas is not an artifact.
7
UI - 21396680
AU - Foster JS; Henley DC; Ahamed S; Wimalasena J
TI -
Estrogens and cell-cycle regulation in breast cancer.
SO - Trends Endocrinol Metab 2001 Sep;12(7):320-7
AD - Dept of OB/GYN, Graduate School of Medicine, University of Tennessee,
Knoxville, TN 37920, USA.
Clinical and experimental data have established that the leading cause
of sporadic female breast cancer is exposure to estrogens, predominantly
17beta-estradiol. Recent advances in the understanding of cell-cycle
control mechanisms have been applied to outline the molecular mechanisms
through which estrogens regulate the cell cycle in cultured breast
cancer cells, in particular, in MCF-7 cells. Here, we discuss how
estrogens exert control over several key G1 phase cell-cycle regulators,
namely cyclin D1, Myc, Cdk2, Cdk4, Cdk inhibitors and Cdc25A. Although
the molecular mechanisms underlying estrogenic regulation of G1 phase
regulators are far from clear, current evidence indicates that estrogens
might regulate several key molecules required for S phase entry, this
regulation being independent of cell-cycle transit per se.
8
UI - 21436642
AU - Coulson AS; Glasspool DW; Fox J; Emery J
TI -
RAGs: A novel approach to computerized genetic risk assessment and
decision support from pedigrees.
SO - Methods Inf Med 2001;40(4):315-22
AD - Advanced Computation Laboratory, Imperial Cancer Research Fund, London,
United Kingdom.
OBJECTIVES: To assist general practitioners in evaluating patients'
genetic risk of cancer on the basis of family history data. METHODS: A
new computer application, RAGs (Risk Assessment in Genetics), has been
developed to help doctors create graphical family trees and assess the
genetic risk of breast and colorectal cancer. RAGs possesses two
features that distinguish it from similar software: (i) a user-centred
design, which takes into account the requirements of the doctor-patient
encounter; (ii) effective and accessible risk reporting by employing
qualitative evidence for or against increased risk, which is more easily
understood than numerical probabilities. The system allows any
rule-based genetic risk guideline to be implemented, and may be readily
modified to cater for the varying degrees of information required by
different specialists. RESULTS: RAGs permits fast, accurate data entry,
and results in more appropriate management decisions than those made via
other techniques. In addition, RAGs enables both the clinician and the
patient to understand how it arrives at its conclusions, since the use
of qualitative evidence allows the program to provide explanations for
its reasoning. CONCLUSIONS: The RAGs system promises to help
practitioners be more effective gatekeepers to genetic services. It may
empower doctors both to make an informed choice when deciding to refer
patients who are at increased genetic risk of breast or colorectal
cancer, and to reassure those who are at low risk.
9
UI - 21446332
AU - Green MJ; Biesecker BB; McInerney AM; Mauger D; Fost N
TI -
An interactive computer program can effectively educate patients about
genetic testing for breast cancer susceptibility.
SO - Am J Med Genet 2001 Sep 15;103(1):16-23
AD - Department of Humanities, Penn State College of Medicine, Hershey,
Pennsylvania 17033, USA. mjg15@psu.edu
As genetic testing for susceptibility to breast cancer becomes more
widespread, alternative methods for educating individuals prior to
testing will be needed. Our objective was to compare face-to-face
education and counseling by a genetic counselor with education by an
interactive computer program, assessing the effects of each on knowledge
of breast cancer genetics and intent to undergo genetic testing. We used
a randomized, controlled trial. Seventy-two self-referred women with a
first-degree relative with breast cancer received outpatient education
and counseling at the Clinical Center of the National Institutes of
Health (NIH). Twenty-nine received individualized counseling from a
genetic counselor (counseling group), 29 received education from an
interactive computer program followed by individualized counseling
(computer group), and 14 were controls. Both pre- and postintervention
assessment of knowledge about breast cancer genetics and intent to
undergo genetic testing were measured. The control group participants
correctly answered 74% of the knowledge questions; the counselor group,
92%; and the computer group, 96% (P <.0001). Unadjusted mean knowledge
scores were significantly higher in the computer group than the
counselor group (P =.048), but they were equivalent when adjusted for
demographic differences (P = 0.34). Intent to undergo genetic testing
was influenced by the interventions: preintervention, a majority in all
groups (69%) indicated that they were likely (definitely and most
likely) to undergo testing; after either intervention coupled with
counseling, only 44% indicated that they were likely to do so (P =.0002;
odds ratio = 2.8, 95% CI = 1.7-4.9). We concluded that a computer
program can successfully educate patients about breast cancer
susceptibility, and, along with genetic counseling, can influence
patients' intentions to undergo genetic testing. Copyright 2001
Wiley-Liss, Inc.
10
UI - 21446333
AU - Green MJ; McInerney AM; Biesecker BB; Fost N
TI -
Education about genetic testing for breast cancer susceptibility:
patient preferences for a computer program or genetic counselor.
SO - Am J Med Genet 2001 Sep 15;103(1):24-31
AD - Department of Humanities, Penn State College of Medicine, Hershey,
Pennsylvania 17033, USA. mjg15@psu.edu
The purpose of this study was to describe and compare patient
preferences for a genetic counselor or an interactive computer program
for various components of genetic education and counseling for breast
cancer susceptibility. As part of a randomized intervention study on
genetics education and counseling for breast cancer risk, 29 women at
moderate risk were educated by both a genetic counselor and an
interactive computer program. After both educational interventions,
participants completed Likert-style and open-ended questionnaires about
what they liked most and least about each intervention, and whether they
preferred the counselor or computer for a variety of tasks. Participants
were largely satisfied with both the computer program and the genetic
counselor. A majority preferred the genetic counselor for addressing
their concerns, discussing options and alternatives, being sensitive to
emotional concerns, helping to make a decision, being a good listener,
assuring understanding, helping to make a good choice, helping to
understand genes and breast cancer, telling them what they needed to
know, being respectful, setting a relaxed tone, and putting them at
ease. However, a majority of the women either preferred the computer
program or were neutral about allowing patients to learn at their own
pace, helping to avoid embarrassment, making good use of time,
explaining genes and breast cancer, and treating the patient as an
adult. Qualitative analysis of open-ended questions affirmed that
patients valued the personal interactions with the counselors, and liked
having their specific questions answered. They liked that the computer
was self-paced, informative and private, and could be used without
causing embarrassment. We concluded that a computer literate, mostly
white group of women at moderate risk for inherited susceptibility to
breast cancer preferred interacting with a genetic counselor for
personal, individualized components of the genetic counseling process,
but accepted or preferred a computer program for being self-paced,
private, and informative. By incorporating such a computer program into
the genetic education process, it is possible that genetic counselors
would be able to spend more time performing the personal, individualized
components of genetic counseling.
11
UI - 21439123
AU - Ghadersohi A; Sood AK
TI -
Prostate epithelium-derived Ets transcription factor mRNA is
overexpressed in human breast tumors and is a candidate breast tumor
marker and a breast tumor antigen.
SO - Clin Cancer Res 2001 Sep;7(9):2731-8
AD - Department of Immunology, Roswell Park Cancer Institute, Buffalo, New
York 14263, USA.
PURPOSE: There is a need to identify novel breast tumor-associated
molecules with a potential as diagnostic/prognostic markers of breast
cancer as well as targets of vaccine and drug discovery against this
cancer. EXPERIMENTAL DESIGN: We used a combination of digital
differential display and reverse transcription-PCR (RT-PCR) methods to
identify breast tumor-associated cDNAs. RESULTS: It was found that
prostate epithelium-derived Ets transcription factor (PDEF) and five
other cDNAs occur at high frequency in the cDNA libraries from normal
human breast tissue and human breast tumors. In contrast, these cDNAs
are either undetectable or present at low frequencies in the cDNA
libraries from other normal human tissues. RT-PCR expression analysis of
PDEF showed it to be overexpressed in 14 of 20 primary human breast
tumors and in one metastases tested. Also, consistent with the digital
differential display data, RT-PCR analysis of PDEF expression showed
highly restricted expression in normal human tissues. Furthermore, we
show that PDEF transcript levels are 192-fold higher in the peripheral
blood of a breast cancer patient in comparison with two normal
individuals and another breast cancer patient. In contrast to PDEF,
RT-PCR analysis of the expression of the other three cDNAs, including
MYL5, Hs.44017, and Hs.215937, showed that these cDNAs are expressed in
several normal human tissues. CONCLUSIONS: These results suggest that
PDEF is a breast tumor-associated cDNA and should be further evaluated
for its potential as a breast tumor marker and a breast tumor antigen.
12
UI - 21439135
AU - Kataoka A; Sadanaga N; Mimori K; Ueo H; Barnard GF; Sugimachi K; Auclair
TI -
D; Chen LB; Mori M
Overexpression of HRad17 mRNA in human breast cancer: correlation with
lymph node metastasis.
SO - Clin Cancer Res 2001 Sep;7(9):2815-20
AD - Department of Surgery, Medical Institute of Bioregulation, Kyushu
University, Beppu 874-0838, Japan.
PURPOSE: A novel human gene, designated HRad17, was identified as the
human homologue of the Rad17 of Schizosaccharomyces pombe and Rad24 of
Saccharomyces cerevisiae. In yeast, these genes play a critical role in
maintaining genomic stability. The aim of this study was to evaluate the
expression of HRad17 in human breast cancer. EXPERIMENTAL DESIGN: We
investigated HRad17 mRNA expression in 64 cases of human breast cancer
by means of reverse-transcription-PCR, in situ hybridization, and
immunohistochemistry. RESULTS: The HRad17 mRNA was overexpressed in 35
cases (54.7%). Twenty-four (68.6%) of 35 cases with HRad17
overexpression in cancer tissues were node-positive, whereas only 8
(27.6%) of 29 cases without HRad17 overexpressions were node-positive.
The expression of HRad17 mRNA correlated with both lymph node metastasis
(P = 0.001) and high Ki67 labeling index (P = 0.006). Although not
significantly different, expression of HRad17 mRNA tended to correlate
with tumor size (P = 0.06) and expression of mutant p53 protein (P =
0.10). Furthermore, expression of HRad17 mRNA was an independent
predictor of axillary lymph node metastasis as well as of lymphatic
permeation by multivariate analysis (P < 0.0001). CONCLUSIONS: Our study
demonstrates that HRad17 might be related to the development of lymph
node metastasis in human breast cancers. Although its function still
remains unclear, the expression of HRad17 mRNA could open up a new
window for the diagnostic staging and treatment of human breast cancers.
13
UI - 21450459
AU - Lahti-Domenici J; Rapakko K; Paakkonen K; Allinen M; Nevanlinna H;
TI -
Kujala M; Huusko P; Winqvist R
Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2
in Finnish breast and ovarian cancer families.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):120-3
AD - Department of Clinical Genetics, University of Oulu/Oulu University
Hospital, P.O. Box 22, FIN-90220, Oulu, Finland.
In the Finnish population, identified mutations in BRCA1 and BRCA2
account for a less than expected proportion of hereditary breast and
ovarian cancer. All previous studies performed in our country have
concentrated on finding germ-line mutations in the coding and
splice-site regions of these two genes. Therefore, we wanted to use a
different methodological approach and search for large genomic
rearrangements, to exclude the possibility of biased BRCA1 and BRCA2
mutation spectra due to known limitations of the previously used
PCR-based detection methods. Our results support earlier notions that
other genes than BRCA1 and BRCA2 will explain a majority of the still
unexplained cases of hereditary susceptibility to breast and ovarian
cancer.
14
UI - 21450463
AU - Hoff C; Mollenhauer J; Waldau B; Hamann U; Poustka A
TI -
Allelic imbalance and fine mapping of the 17p13.3 subregion in sporadic
breast carcinomas.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):145-9
AD - Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum,
Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Chromosome arm 17p is frequently altered in a variety of human cancers,
especially in breast cancer, and allelic imbalances (AIs) in the region
17p13.1 do not always coincide with mutations in the TP53 gene. A second
interval that frequently shows AIs at 17p is the chromosomal band
17p13.3. This region is suspected to harbor another tumor suppressor
gene. In order to get more information concerning the pattern of AIs in
17p13.3, we performed analysis of AI of 49 breast carcinomas at 6
polymorphic loci in 17p13.3. Eighty-six percent of the tumors present AI
at least at one marker in 17p13.3. Among all loci tested, the highest
percentage of Al was observed at loci D17S5 (77%) and D17S1528 (72%).
According to these results, a minimal region of deletion could be
determined between the markers D17S28 and D17S5. Fine mapping of this
region revealed that the size of the deleted region is about 100-150 kb.
Furthermore, a subset of the patients shows two other areas with AI
close to the markers D17S1574/D17S513 and D17S849, respectively.
15
UI - 21468601
AU - Gershoni-Baruch R; Dagan E; Israeli D; Kasinetz L; Kadouri E; Friedman E
TI -
Association of the C677T polymorphism in the MTHFR gene with breast
and/or ovarian cancer risk in Jewish women.
SO - Eur J Cancer 2000 Dec;36(18):2313-6
AD - Institute of Human Genetics, Rambam Medical Center, Haifa, Israel.
rgershoni@rambam.health.gov.il
The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR)
gene is associated with reduced enzyme activity, hyperhomocysteinaemia
and increased risk for atherosclerosis in homozygotes. We examined the
frequency of this mutation and its association with disease pattern in
491 Jewish women with either sporadic (n = 355; 72%) or hereditary (n =
136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2
mutation carriers, genotyped for the three predominant Jewish founder
BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes
were equally distributed among women with sporadic breast and/or ovarian
cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205;
21.0%) (P=non-significant). 677T homozygotes were equally distributed
among women diagnosed with breast cancer prior to (22/122; 18.0%) and
after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate
of 677T homozygotes in manifesting cancer (32/136; 23.5%) and
asymptomatic individuals (11/69; 15.9%) was not significantly different.
The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among
women with bilateral breast cancer and those with both breast and
ovarian carcinoma than among those with unilateral breast cancer
(64/365; 17.5%). Differences in morbidity (one versus multiple
breast/ovarian tumours) are mainly attributed to 677T homozygosity and
partly to BRCA1/2 mutations. Confirmation of these data, namely, that
the 677T allele is significantly more common in cases of bilateral
breast cancer or combined breast and ovarian cancer would have important
clinical implications.
16
UI - 21468609
AU - Miyoshi Y; Iwao K; Ikeda N; Egawa C; Noguchi S
TI -
Genetic polymorphism in CYP17 and breast cancer risk in Japanese women.
SO - Eur J Cancer 2000 Dec;36(18):2375-9
AD - Department of Surgical Oncology, Osaka University Medical School,
Suita-shi, Japan.
A case-control study was conducted to investigate the association of two
genetic polymorphisms (1931T/C and 1951G/A) in the promoter region of
the CYP17 gene with breast cancer risk in Japanese women. No significant
association was observed between CYP17 polymorphism(1951G/A) and breast
cancer risk (odds ratio (OR) = 1.71, 95% confidence interval (CI):
0.28-1.84). In contrast, a significant increase in breast cancer risk
(OR= 1.82. 95% CI: 1.07-3.12) was observed in CYP17(1931C/C) homozygotes
compared with CYP17(1931T/C) heterozygotes and CYP17(1931T/T)
homozygotes when women aged > or = 55 years were considered, but such a
significant increase was not observed when women aged < or = 54 years
were considered (OR = 0.96, 95% CI: 0.56-1.63). These results suggest
that CYP17 polymorphism(1931T/C) would be useful in the selection of
Japanese women at a high risk for developing breast cancer at the age of
> or = 55 years.
17
UI - 21218915
AU - Jacquemier J; Lidereau R; Birnbaum D; Eisinger F; Sobol H
TI -
Assessing the risk of BRCA1-associated breast cancer using individual
morphological criteria.
SO - Histopathology 2001 Apr;38(4):378-9
18
UI - 21262969
AU - Roy SK; Trividi AH; Bakshi SR; Patel SJ; Shukla PS; Shah AD; Majithiya
TI -
DB; Patel DD; Shah PM
A study of chromosome aneuploidy in hereditary breast cancer patients
and their healthy blood relatives.
SO - J Exp Clin Cancer Res 2001 Mar;20(1):103-9
AD - Dept. of Surgical Oncology, The Gujarat Cancer Society, Asarwa,
Ahmedabad, India. shambhu@mail.ucr.edu
Chromosomal abnormalities that may predispose a group of individuals to
develop certain neoplasms have been reported in lymphocytes. We
evaluated cytogenetic abnormalities in 21 histopathologically confirmed
primary breast cancer patients (BCPs), 52 healthy blood relatives
(HBRs), belonging to 19 hereditary breast cancer families (HBFs) and 25
females as control. Phytohemagglutinin stimulated peripheral blood
lymphocyte (PBL) cultures were used to study the chromosomal
abnormalities in BCPs and their HBRs. Short term culture of the tumor
tissue was also carried out in defined growth medium. Suitable
metaphases (11 to 55) from tumors and a minimum of 100 metaphases from
PBL were karyotyped for the cytogenetic analysis. Heterogeneous
population of cells with random and nonrandom chromosomal abnormalities
was noticed in tumors. In control groups 2-5% of metaphases showed
numerical abnormalities, whereas this phenomenon was observed in 3-18%
of metaphases in HBRs and 3-23% of metaphases in BCPs. In tumor tissue,
47.05% of BCPs showed numerical abnormalities in more than 16
metaphases. In lymphocytes, this event was observed in 33.33% of BCPs
and 13.14% of HBRs. In controls 1.28%, in BCPs 52.04% (tumor) and 13.42%
(lymphocytes), and in HBRs 9.03% of metaphases were found aneuploid.
Statistically it was highly significant (Fisher's exact test,
P<0.00001). In lymphocytes of BCPs, chromosomes 1, 6, 8, 9, 15, 17, 18,
20, and X and in HBRs, chromosomes 8, 15, 17, 18, and X were frequently
involved. It can be inferred from the findings that the above mentioned
chromosomes may have an important role in early stage of breast
carcinogenesis in BCFs. Moreover, presence of similar abnormalities in
HBR indicates inherited pattern of this genetic error among them.
19
UI - 21283055
AU - Bergthorsson JT; Ejlertsen B; Olsen JH; Borg A; Nielsen KV; Barkardottir
TI -
RB; Klausen S; Mouridsen HT; Winther K; Fenger K; Niebuhr A; Harboe TL;
Niebuhr E
BRCA1 and BRCA2 mutation status and cancer family history of Danish
women affected with multifocal or bilateral breast cancer at a young
age.
SO - J Med Genet 2001 Jun;38(6):361-8
AD - Department of Medical Genetics, Institute for Medical Biochemistry and
Genetics, Panum Institute, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
nonni@rsp.is
INTRODUCTION: A small fraction of breast cancer is the result of
germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes.
Mutation carriers frequently have a positive family history of breast
and ovarian cancer, are often diagnosed at a young age, and may have a
higher incidence of double or multiple primary breast tumours than
breast cancer patients in general. OBJECTIVES: To estimate the
prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish
patients affected with bilateral or multifocal breast cancer and to
determine the relationship of mutation status to family history of
cancer. SUBJECTS: From the files of the Danish Breast Cancer Cooperative
Group (DBCG), we selected 119 breast cancer patients diagnosed before
the age of 46 years with either bilateral (n=59) or multifocal (n=61)
disease. METHODS: DNA from the subjects was screened for BRCA1 and BRCA2
mutations using single strand conformation analysis (SSCA) and the
protein truncation test (PTT). Observed and expected cancer incidence in
first degree relatives of the patients was estimated using data from the
Danish Cancer Registry. RESULTS: Twenty four mutation carriers were
identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2
mutation. Two mutations in BRCA1 were found repeatedly in the material
and accounted for seven of the 24 (29%) mutation carriers. The mutation
frequency was about equal in patients with bilateral (22%) and
multifocal breast cancer (18%). The incidence of breast and ovarian
cancer was greatly increased in first degree relatives of BRCA1 and
BRCA2 mutation carriers, but to a much lesser degree in relatives of
non-carriers. An increased risk of cancer was also noted in brothers of
non-carriers. CONCLUSIONS: A relatively broad spectrum of germline
mutations was observed in BRCA1 and BRCA2 and most of the mutations are
present in other populations. Our results indicate that a diagnosis of
bilateral and multifocal breast cancer is predictive of BRCA1 and BRCA2
mutation status, particularly when combined with information on the
patients' age at diagnosis and family history of breast/ovarian cancer.
20
UI - 21317608
AU - Gad S; Scheuner MT; Pages-Berhouet S; Caux-Moncoutier V; Bensimon A;
TI -
Aurias A; Pinto M; Stoppa-Lyonnet D
Identification of a large rearrangement of the BRCA1 gene using
colour bar code on combed DNA in an American breast/ovarian cancer
family previously studied by direct sequencing.
SO - J Med Genet 2001 Jun;38(6):388-92
21
UI - 21468783
AU - Magnet KJ; Orr MS; Cleveland JL; Rodriguez-Galindo C; Yang H; Yang C; Di
TI -
YM; Jain PT; Gewirtz DA
Suppression of c-myc expression and c-Myc function in response to
sustained DNA damage in MCF-7 breast tumor cells.
SO - Biochem Pharmacol 2001 Sep 1;62(5):593-602
AD - Department of Medicine, Medical College of Virginia at Virginia
Commonwealth University, Richmond 23298-0230, USA.
The topoisomerase II inhibitors teniposide (VM-26), doxorubicin, and
amsacrine (m-AMSA), as well as ionizing radiation, induce a transient
suppression of c-myc mRNA, which correlates with growth inhibition of
MCF-7 breast tumor cells. To further assess the involvement of c-mvc in
the DNA damage-induced signal transduction pathways of the breast tumor
cell, we determined the influence of sustained DNA damage on c-myc
expression, c-Myc protein levels and c-Myc function. Continuous exposure
of MCF-7 breast tumor cells to VM-26 induced DNA strand breaks that were
sustained for at least 9 hr. DNA strand breakage was accompanied by a
decline in c-myc transcripts and c-Myc protein levels by >90% after
VM-26 exposure for 24 hr. The activity of a transcriptional target of
the c-Myc protein, ornithine decarboxylase, was reduced by approximately
75% within 9 hr of DNA damage, in parallel to the declines in c-myc mRNA
and protein levels. Extended exposure to VM-26 resulted in an initial
loss of approximately 35% of the cell population followed by the death
of additional cells such that by 72 hr only 50% of the cells were
viable. Although apoptosis was evident 72 hr after initiating drug
exposure [based on cell cycle analysis, terminal deoxynucleotidyl
transferase-mediated dUTP nick end-labeling (TUNEL) assays, and an
assessment of cell morphology], the primary phase of cell killing, which
occurred during the first 24 hr was non-apoptotic. These studies
indicate that non-apoptotic pathways can also mediate cell death in the
breast tumor cell and support the role of c-myc expression, c-Myc
protein, and c-Myc function as elements of the DNA damage response
pathway in the breast tumor cell.
22
UI - 99296429
AU - Shevde LA; Joshi NN; Advani SH; Nadkarni JJ
TI -
Impaired T lymphocyte function and differential cytokine response
pattern in members from cancer families.
SO - Nat Immun 1998;16(4):146-56
AD - Immunology Division, Cancer Research Institute, Parel, Mumbai, India.
In an attempt to understand the basis of lowered natural killer (NK) and
T cell functions in unaffected members from cancer families, we
investigated cytotoxic T lymphocyte function (CD3-directed lysis) and
the ability of the lymphocytes to respond to cytokines such as IL-2,
IFN-alpha and IL-12. We observed lower CD3-mediated cytotoxic activity
in these individuals supported by significantly lower numbers of
circulating CD3+ lymphocytes. The cytokine treatment studies revealed
impaired response to IFN-alpha and IL-12 in unaffected members and
breast cancer patients. The observations presented herein not only
reinforce our earlier finding that lower NK and T lymphocyte function
may be a feature of cancer families, but also suggest that such impaired
responses may be one of the factors contributing to lower cytotoxic
potential of the circulating lymphocytes.
23
UI - 21443275
AU - Otte M; Zafrakas M; Riethdorf L; Pichlmeier U; Loning T; Janicke F;
TI -
Pantel K
MAGE-A gene expression pattern in primary breast cancer.
SO - Cancer Res 2001 Sep 15;61(18):6682-7
AD - Molekulare Onkologie, Frauenklinik, Universitatsklinikum
Hamburg-Eppendorf, Germany.
Melanoma antigen (MAGE)-A-derived peptides elicit a strong in vitro
T-cell response against tumor cells. For determination of MAGE-A1, -2,
-3, -4, -6, and -12 expression profile in invasive breast cancer, we
developed a multiplex seminested reverse transcription-PCR-method. In
total, 18 of 67 (27%) tumors were positive for at least one of these
MAGE transcripts, and the expression pattern was heterogeneous: MAGE-A1
was positive in 4 of 67 (6%), MAGE-A2 in 13 of 67 (19%), MAGE-A3 in 7 of
67 (10%), MAGE-A4 in 9 of 67 (13%), MAGE-A6 in 10 of 67 (15%), and
MAGE-A12 in 6 of 67 (9%) patients. The MAGE-A transcripts were more
frequently expressed in ductal breast carcinomas compared with other
histomorphological types. We observed a preferential expression of
MAGE-A in patients at a higher risk of recurrence: those harboring
tumors with high levels of the protease urokinase-type plasminogen
activator and its inhibitor plasminogen activator inhibitor 1, high
score of the Ki-67 proliferation antigen, and lesser degree of
differentiation. Our findings suggests a potential involvement of MAGE-A
in tumor progression, with potential implications for active
immunotherapy.
24
UI - 21443287
AU - Lu D; Kiriyama Y; Lee KY; Giguere V
TI -
Transcriptional regulation of the estrogen-inducible pS2 breast cancer
marker gene by the ERR family of orphan nuclear receptors.
SO - Cancer Res 2001 Sep 15;61(18):6755-61
AD - Molecular Oncology Group, McGill University Health Centre, Montreal,
Quebec, H3A 1A1 Canada.
The estrogen-receptor-related receptors (ERRs) alpha, beta, and gamma
are orphan nuclear hormone receptors that share significant homology
with the estrogen receptors (ERs) but are not activated by natural
estrogens. In contrast, the ERRs display constitutive transcriptional
activity in the absence of exogenously added ligand. However, the ERRs
bind to the estrogen response element and to the extended half-sites of
which a subset can also be recognized by ERalpha, suggesting that ERRs
and ERs may control overlapping regulatory pathways. To test this
hypothesis, we explored the possibility that ERRs could regulate the
expression of the estrogen-inducible pS2 gene, a human breast cancer
prognostic marker. Transfection studies show that all of the ERR
isoforms can activate the pS2 promoter in a variety of cell types,
including breast cancer cell lines. Surprisingly, sequence analysis
combined with mutational studies revealed that, in addition to the
well-characterized estrogen response element, the presence of a
functional extended half-site within the pS2 promoter is also required
for complete response to both ER and ERR pathways. We show that ERR
transcriptional activity on the pS2 promoter is considerably enhanced in
the presence of all three members of the steroid receptor coactivator
family but is completely abolished on treatment with the synthetic
estrogen diethylstilbestrol, a recently described inhibitor of ERR
function. Finally, we demonstrate that ERRalpha is the major isoform
expressed in human breast cancer cell lines and that diethylstilbestrol
can inhibit the growth of both ER-positive and -negative cell lines.
Taken together, these results demonstrate that estrogen-inducible genes
such as pS2 can be ERR targets and suggest that pharmacological
modulation of ERRalpha activity may have therapeutic value in the
treatment of breast cancer.
25
UI - 21459561
AU - Ray GN; Shahid M; Husain SA
TI -
Effect of nitric oxide and malondialdehyde on sister-chromatid exchanges
in breast cancer.
SO - Br J Biomed Sci 2001;58(3):169-76
AD - Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Nitric oxide (NO) and malondialdehyde (MDA) play a significant role in
DNA damage, sister-chromatid exchanges (SCEs) and carcinogenesis. Here,
we determine plasma NO and MDA to evaluate their role in carcinogenesis
and their effect on the frequency of SCEs in 45 female breast cancer
patients and in 35 age- and sex-matched controls. Plasma NO (P<0.01) and
MDA (P<0.001) was significantly higher in the breast cancer group, and a
direct correlation were found between plasma NO and MDA concentration
and tumour grade. Patients with stage II disease showed the highest
levels of both NO and MDA, compared with controls. Simultaneously, SCE
frequency per lymphocyte in the breast cancer group was found to be
significantly (P<0.001) higher; the greatest increase being found in
patients with stage IV disease. Positive correlation was found between
SCEs and both NO and MDA in the breast cancer group; however, both NO
and MDA production decreased with increasing severity of the disease.
Lower NO production in stage IV disease may be due to lower expression
of nitric oxide synthase (NOS), further facilitating the production of
superoxide anions (O2*-). The reaction between NO and O2*- results in
peroxynitrite (OONO-) formation, which works efficiently at the
molecular level and may induce higher SCE frequency. This work suggests
that further cytogenetic and molecular study is required to provide
definite answers for the therapeutic use of NO in breast cancer.
26
UI - 20483334
AU - Gao Q; Tomlinson G; Das S; Cummings S; Sveen L; Fackenthal J; Schumm P;
TI -
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