National Cancer Institute®
Last Modified: May 1, 2002
UI - 11768600
AU - Elhaji YA; Gottlieb B; Lumbroso R; Beitel LK; Foulkes WD; Pinsky L;
TI - Trifiro MA The polymorphic CAG repeat of the androgen receptor gene: a potential role in breast cancer in women over 40.
SO - Breast Cancer Res Treat 2001 Nov;70(2):109-16
AD - Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Previous investigations into the relationship of CAG-repeat lengths in the androgen receptor (AR) gene to female breast cancer (BC) have yielded somewhat confusing results. Decreased AR transactivational activity lowers androgen:estrogen balance, and may thereby effect functional hyperestrogenicity. This may promote the pathogenesis of BC. To elucidate whether longer CAG repeats of the AR gene (AR), which correlate with lower transactivational activity of the AR, are associated with BC in women over 40, we examined the distribution of CAG-repeat lengths in BC tissue from this population. The BC tissue was histologically graded as: Grade 1, well differentiated (WD); Grade 2, moderately differentiated (MD); and Grade 3, poorly-differentiated (PD). Analysis showed significant differences as compared to controls when CAG lengths greater than 21 were examined, and that alleles with > or = 26 repeats were 2.4-fold more frequent in BC samples than in constitutional samples from a normal population. A significant shift to greater CAG-repeat lengths, appeared in WD and MD tumors only. Our results give some indication as to the progression of BC by suggesting that hypotransactive ARs with long polyglutamine (polyGln) tracts may have a role in the initiation and/or progression of BC. PD tumors tended to have shorter than normal CAG-repeat lengths. In this case it is hypothesized that the ARs have now become hypertransactive, possibly coinciding with the estrogen resistance that is associated with PD tumors. Whether this shift is of germline or somatic origin was not clear, though the appearance in 14% of the BC samples of a third CAG-repeat length indicates that it may be somatic.
UI - 11768601
AU - Yu H; Li BD; Smith M; Shi R; Berkel HJ; Kato I
TI - Polymorphic CA repeats in the IGF-I gene and breast cancer.
SO - Breast Cancer Res Treat 2001 Nov;70(2):117-22
AD - Feist-Weiller Cancer Center and Department of Medicine, Louisiana State University Health Sciences Center, Shreveport 71130-3932, USA. email@example.com
Insulin-like growth factor (IGF)-I is a potent mitogen for breast cancer cells and may play a role in the disease. Although the involvement of IGF-I phenotype in breast cancer has been studied extensively, little is known about IGF-I genotype in relation to the disease. The IGF-I gene contains a polymorphic region composed of multiple cytosine-adenine dinucleotides (CA repeats). Studies of other genes indicate that the CA-repeat region in the promoter of a gene may affect transcription activity and that the length of the repeat is inversely correlated with transactivation. To examine if the IGF-I polymorphism is associated with breast cancer, we compared the length of CA repeats in the IGF-I gene between 53 breast cancer patients and 53 controls. Genomic DNA extracted from peripheral blood was used to determine the number of CA repeats through PCR amplification and DNA sequencing. Associations between CA repeats and breast cancer were assessed using unconditional logistic regression analysis. The results showed that the median number of CA repeats was 19, ranging from 15 to 23, and that compared to women without 19 CA repeats, women with 19 CA repeats were more likely to be breast cancer patients (OR = 2.87, 95%CI: 1.16-7.06) after adjusting for age, race, menopausal status, age at menopause, and alcohol use. The study also suggested possible synergistic interplay between IGF-I genotype and phenotype as women with 19 CA repeats and high plasma IGF-I had a much higher odds ratio for breast cancer (OR = 5.12, 95%CI: 1.42-18.5) than those with only one of the conditions. If our observations can be confirmed in larger studies, the findings will provide further evidence to support the role of IGF-I in breast cancer and the link between genetic polymorphism and cancer susceptibility.
UI - 11809729
AU - Iwao K; Matoba R; Ueno N; Ando A; Miyoshi Y; Matsubara K; Noguchi S;
TI - Kato K Molecular classification of primary breast tumors possessing distinct prognostic properties.
SO - Hum Mol Genet 2002 Jan 15;11(2):199-206
AD - Taisho Laboratory of Functional Genomics, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0101, Japan.
The natural progression of breast cancer differs greatly between patients; the precise prediction of this disease course will improve the efficacy of therapeutics. Gene expression profiling may elucidate the undiscovered biological variations between seemingly similar cancers, leading to a new cancer classification system valuable in accurate diagnosis. The expression levels of 2412 genes, derived from 98 cancer samples, were precisely recorded by a high throughput RT-PCR technique, adapter-tagged competitive PCR. Subsequent cluster analysis revealed a molecular profile, correlating with estrogen receptor levels and the presence of lymph node metastases. We analyzed 301 cancer samples for the expression patterns of 21 genes critical in this categorization. The classification of the samples into three major groups was verified utilizing principal component analysis. This molecular classification system correlated significantly with early recurrence, independent of lymph node status. This malignant potential is associated with the expression levels of a group of genes, which comprise a set of candidates potentially useful in diagnostic prediction. These genes and the associated control mechanisms may also be effective therapeutic targets.
UI - 11840198
AU - Miedzybrodzka Z; Hamilton NM; Gregory H; Milner B; Frade I; Sinclair T;
TI - Mollison J; Haites N Teaching undergraduates about familial breast cancer: comparison of a computer assisted learning (CAL) package with a traditional tutorial approach.
SO - Eur J Hum Genet 2001 Dec;9(12):953-6
AD - Department of Medicine & Therapeutics, University of Aberdeen, Aberdeen, UK. firstname.lastname@example.org
We have developed a computer assisted learning package for teaching clinical medical students about familial breast cancer. It explains the principles of genetic predisposition to breast cancer, the association with other cancers, the principles of family history taking and confirmation, risk assessment and possible interventions. Clinical medical students were randomised to either conventional teaching or CAL, 48 students attended the evaluation session. Students randomised to conventional teaching received a 20 min mini-lecture, those randomised to CAL completed the package with technical, but not academic support available. At the end of the intervention both groups of students completed a short written assessment of acceptability and knowledge and understanding of breast cancer genetics. There was no significant difference between the CAL and mini-lecture groups in terms of marks or acceptability. Thus CAL appears to be an acceptable and effective method of teaching clinical medical students about familial breast cancer. Although time consuming to develop, CAL can be used in a variety of settings to increase curriculum flexibility. Methods of motivating students to complete the CAL, and of providing educational support are being explored.
UI - 11818203
AU - Omoto Y; Kobayashi S; Inoue S; Ogawa S; Toyama T; Yamashita H; Muramatsu
TI - M; Gustafsson JA; Iwase H Evaluation of oestrogen receptor beta wild-type and variant protein expression, and relationship with clinicopathological factors in breast cancers.
SO - Eur J Cancer 2002 Feb;38(3):380-6
AD - Department of Surgery II, Nagoya City University Medical School, 1 Kawasumi, Mizuho-ku, 467-8601, Nagoya, Japan. email@example.com
We addressed the clinicopathological significance of the oestrogen receptor (ER) beta protein, including an ERbeta variant, ERbetacx, in normal human breast and breast cancer. The reverse transcriptase-polymerase chain reaction (RT-PCR) showed that wild-type ERbeta (ERbetaw) mRNA expression was higher in normal than cancer tissues, and that ERbetacx mRNA was higher in cancer than in normal tissues. Immunohistochemistry of 22 normal breast tissues and 57 breast cancers was performed with three different ERbeta antibodies and one ERbetacx antibody. All normal breast samples showed staining with the three ERbeta antibodies, suggesting that ERbetaw might have a physiological role in oestrogen signalling in the normal breast. In breast cancer, expression of the ERbetaw protein correlated well with the expression of the ERalpha and progesterone receptor (PgR), as well as histological grade (HG), and tended to indicate a better prognosis than when ERbetaw was absent. Thirty-one (54%) breast cancer samples contained ERbetacx, whereas the corresponding tissue for normal breast samples stained positive in only two (9%).
UI - 11929806
AU - Li Z; Meng ZH; Chandrasekaran R; Kuo WL; Collins CC; Gray JW; Dairkee SH
TI - Biallelic inactivation of the thyroid hormone receptor beta1 gene in early stage breast cancer.
SO - Cancer Res 2002 Apr 1;62(7):1939-43
AD - Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco, California 94115, USA.
Loss of heterozygosity within the short arm of chromosome 3 is a common molecular event in several types of solid tumors. In breast cancer, 3p loss of heterozygosity occurs in invasive tumor cells as well as in morphologically normal terminal ductal lobular units adjacent to carcinoma in some cases [G. Deng et al., Science (Wash. DC), 274: 2057-2059, 1996.]. The most frequent region of allelic loss at 3p24.3 in morphologically normal terminal ductal lobular units encompasses the thyroid hormone receptor beta1 (TRbeta1) gene. Here we have observed a variable degree of TRbeta1 promoter hypermethylation in all 11 cases of primary breast cancer examined. Moreover, hypermethylation occurred at the same CpG sites in nonmalignant tissue peripheral to carcinoma in 4 of 11 cases. The lack of TRbeta1 nuclear staining, a likely result of biallelic gene inactivation, was observed in 25% (22 of 85) of primary tumors. This is a first demonstration of promoter hypermethylation and a concurrent reduction of TRbeta1 transcripts in breast cancer cell lines, although specific CpG sites targeted for gene silencing remain to be determined. Gene expression was restored by treatment with 5-aza-deoxycytidine in such cases. The observation of early, frequent, and multiple mechanisms of TRbeta1 inactivation suggests a potential role for this gene in the suppression of breast tumorigenesis.
UI - 11929815
AU - Conway K; Edmiston SN; Cui L; Drouin SS; Pang J; He M; Tse CK; Geradts
TI - J; Dressler L; Liu ET; Millikan R; Newman B Prevalence and spectrum of p53 mutations associated with smoking in breast cancer.
SO - Cancer Res 2002 Apr 1;62(7):1987-95
AD - Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. firstname.lastname@example.org
To explore the role of smoking in breast cancer, we undertook a population-based study to evaluate the prevalence and spectrum of p53 mutations in the breast tumors of smokers and nonsmokers. We evaluated 456 archival invasive breast tumors for mutations in exons 4-8 of the p53 gene, using single-strand conformational polymorphism analysis and manual sequencing. Statistical analyses were performed to determine the association of p53 mutations with clinical and smoking characteristics. Of 108 mutations identified, 77 (71%) were point mutations and 31 (29%) were deletions or insertions. A higher prevalence of p53 mutations was found in the breast tumors of current smokers (36.5%; P = 0.02) compared with never smokers (23.6%), whereas fewer mutations were found in former smokers (16.2%; P = 0.09). After adjustment for age, race, menopausal status, clinical stage, tumor size, and family history of breast cancer, current smokers were significantly more likely to harbor any p53 mutation [odds ratio (OR), 2.11; 95% confidence interval (CI), 1.17-3.78], p53 transversions (OR, 3.37; 95% CI, 1.03-11.06), and G:C-->T:A transversions (OR, 10.53; 95% CI, 1.77-62.55) compared with never smokers. Stage at diagnosis did not account for the increase in p53 mutation-positive breast cancer among current smokers. Former smokers were also more likely than never smokers to harbor G:C-->T:A transversions (OR, 2.43; 95% CI, 0.37-15.73), although this association was not statistically significant. Among former smokers, the prevalence of p53 mutations varied with time since quitting: former smokers who quit smoking for longer than 1 year had a lower prevalence of p53 mutations (10.5% for 1-5 years and 12.9% for >5 years) than those who had stopped smoking within the year of their cancer diagnosis (26.3%). Our results indicate that cigarette smoking appears to modify the prevalence and spectrum of p53 mutations in breast tumors. Moreover, the difference in mutational spectra observed between smokers and nonsmokers is suggestive of the genotoxic effects of smoking in breast tissue.
UI - 11929828
AU - Bearss DJ; Lee RJ; Troyer DA; Pestell RG; Windle JJ
TI - Differential effects of p21(WAF1/CIP1) deficiency on MMTV-ras and MMTV-myc mammary tumor properties.
SO - Cancer Res 2002 Apr 1;62(7):2077-84
AD - Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
p21(WAF1/CIP1) (p21) functions as a cyclin-dependent kinase (CDK) inhibitor and is a key mediator of p53-dependent growth arrest. However, its role in cell cycle regulation is complex, because it also appears to promote CDK activity in certain experimental contexts. Its potential role in tumor suppression was evaluated in MMTV-ras and MMTV-myc transgenic mice that were interbred to p21(WAF1/CIP1) knockout mice (p21-/-). p21 deficiency had differential effects on tumor incidence and age of onset, proliferation, and apoptosis in the presence of these two oncogenes. Tumors arising in MMTV-ras/p21-/- mice displayed higher S-phase fractions and correspondingly increased cyclin D1 and E/CDK activity than MMTV-ras tumors. In contrast, MMTV-myc/p21-/- tumors had lower S-phase fractions and levels of cyclin D1 and E/CDK activity than MMTV-myc tumors. In both tumor types, changes in cyclin D1 and E/CDK activity were paralleled by changes in the corresponding cyclin protein levels. Tumor cell apoptosis was also differentially influenced by p21 deficiency in the two models. MMTV-ras/p21-/- tumors exhibited a significant increase in spontaneous apoptosis as compared with MMTV-ras tumors, whereas p21 deficiency had minimal effect on apoptosis in MMTV-myc tumors. These results indicate that the effects of p21 expression on cellular proliferation are differentially affected by the expression of different oncogenes, and that p21 may play a role in promoting either growth arrest or proliferation, depending on the specific cellular context.
UI - 11935298
AU - Kroll T; Odyvanova L; Clement JH; Platzer C; Naumann A; Marr N; Hoffken
TI - K; Wolfl S Molecular characterization of breast cancer cell lines by expression profiling.
SO - J Cancer Res Clin Oncol 2002 Mar;128(3):125-34
AD - Clinic for Internal Medicine II (Hematology, Oncology, Metabolic Diseases and Diabetes), Friedrich-Schiller-University Jena, Erlanger Allee 101, 07740 Jena, Germany.
PURPOSE: Gene expression patterns provide detailed insights into cellular regulation that reflect minor differences of cellular capacity not accessible by standard descriptions of the cellular phenotype or origin. METHODS: To identify fundamental differences and similarities we analyzed the gene expression patterns of four breast cancer cell lines: MCF-7, SK-BR-3, T-47D, and BT-474. RESULTS: Although only a small subset of genes (597) is represented on the Atlas-cDNA-Array (Clontech) used, clear differences in the expression of a number of genes could be detected. For example, unique high levels of expressions were found for the HLH-protein ID-1 (MCF-7) and the receptor tyrosine kinase erbB2 (SK-BR-3 and T-47D). Most genes analyzed were expressed at comparable levels in all cell lines studied. CONCLUSIONS: For interpretation of the results sets of genes that show similar variation of expression among the cells were grouped together. Furthermore, our analysis allows the assignment of similarity values that lead to a relation profile of the cell lines. How these results correlate with known biological properties of the cell lines is discussed. Additionally, we demonstrate that results obtained by cDNA-Array hybridization for expression of the ErbB receptor family correlate well with competitive RT-PCR, thus confirming the reliability of the cDNA-Array analysis.
UI - 11935306
AU - Berstein LM; Larionov AA; Poroshina TE; Zimarina TS; Leenman EE
TI - Aromatase (CYP19) expression in tumor-infiltrating lymphocytes and blood mononuclears.
SO - J Cancer Res Clin Oncol 2002 Mar;128(3):173-6
AD - Lab. of Oncoendocrinology, Prof. N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia. email@example.com
PURPOSE: To clarify the role of lymphocytes as a possible source of estrogens. METHODS: In the present study, lymphocytes were isolated from 11 surgical samples of breast cancer after tumor enzyme digestion and Ficoll/Verographine procedure. Simultaneously, using the latter procedure, mononuclears were separated from the blood of 15 female volunteers. RESULTS: Expression of the aromatase (CYP19) gene was readily demonstrated by standard RT-PCR in blood mononuclears cultivated in the presence of 10% fetal calf serum for 48 h. In the tumor-infiltrating lymphocytes (TIL) of breast cancer patients, CYP19 expression was discovered only with the aid of nested PCR. CONCLUSIONS: The data obtained suggest that aromatase gene expression is presented in TIL at a rather low level. Nevertheless, this can have some functional significance for the estrogen-dependent growth of breast cancer tissue.
UI - 11867202
AU - Kang HJ; Kim SW; Kim HJ; Ahn SJ; Bae JY; Park SK; Kang D; Hirvonen A;
TI - Choe KJ; Noh DY Polymorphisms in the estrogen receptor-alpha gene and breast cancer risk.
SO - Cancer Lett 2002 Apr 25;178(2):175-80
AD - Department of Surgery, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, South Korea.
The estrogen receptor-alpha (ERalpha) has been known to play a role in the development and progression of breast cancer. Several genetic polymorphisms in the ERalpha gene have been related to breast cancer risk and/or different tumor characteristics. In this study, PCR and direct sequencing based methods were used to examine this issue further in a Korean study population consisting of 155 women, 110 with breast cancer and 45 without cancer. We also assessed the potential role of the ERalpha genotype in ER, PR, p53, c-erbB2, and bcl-2 expression. Only one of the allelic variants of ERalpha gene was found in our study subjects; the (C(975)G) change was present in half of the study subjects. Although this allele had no direct effect in individual breast cancer risk, it was positively associated with tumor PR (P for trend=0.04) and ER expression (P for trend=0.06) and negatively associated with p53 expression (P for trend=0.02).
UI - 11879563
AU - McAllister KA; Wiseman RW
TI - Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?
SO - Breast Cancer Res 2002;4(2):54-7
AD - Laboratory of Women's Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. firstname.lastname@example.org
Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous delta11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated.
UI - 11879567
AU - Gasco M; Shami S; Crook T
TI - The p53 pathway in breast cancer.
SO - Breast Cancer Res 2002;4(2):70-6
AD - Department of Surgery, Oldchurch Hospital, Romford, UK.
p53 mutation remains the most common genetic change identified in human neoplasia. In breast cancer, p53 mutation is associated with more aggressive disease and worse overall survival. The frequency of mutation in p53 is, however, lower in breast cancer than in other solid tumours. Changes, both genetic and epigenetic, have been identified in regulators of p53 activity and in some downstream transcriptional targets of p53 in breast cancers that express wild-type p53. Molecular pathological analysis of the structure and expression of constituents of the p53 pathway is likely to have value in diagnosis, in prognostic assessment and, ultimately, in treatment of breast cancer.
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.
UI - 11588905
AU - Buzin CH; Tang SH; Cunningham JM; Shibata A; Ross RK; Hartmann A;
TI - Blaszyk H; Kovach JS Low frequency of p53 gene mutations in breast cancers of Japanese-American women.
SO - Nutr Cancer 2001;39(1):72-7
AD - Division of Molecular Medicine, City of Hope Beckman Research Institute and National Medical Center, Duarte, CA 91010, USA.
Differences in frequencies and patterns of somatic p53 gene mutations among racially and geographically diverse populations presumably reflect exposure to different mutagens or different responses to certain mutagens. On emigration to the United States, Japanese women experience, over several generations, a four- to fivefold increase in the incidence of breast cancer. To determine whether this increased incidence is associated with a change in the frequency and/or type of p53 mutation in their tumors, we examined paraffin-embedded samples of primary breast cancers from Japanese-American women in Los Angeles County, CA. Mutations in exons 5-9 and adjacent intronic regions of the p53 gene were identified and confirmed by direct sequencing. Seven mutations, including 5 missense, were detected in 44 primary breast carcinomas, a frequency of 16%. There were six transitions and one transversion. As expected, overexpression of p53 protein, detected by immunohistochemistry, occurred in tumors with missense mutations; tumors with nonsense or splice junction mutations had no detectable p53 protein. The frequency of p53 gene mutations showed no increase over that previously found in breast cancers of native Japanese women. The increased incidence of breast cancer in Japanese-American women is likely to be multifactorial in nature and warrants further studies.
UI - 11788792
AU - Lee EJ; Jakacka M; Duan WR; Chien PY; Martinson F; Gehm BD; Jameson JL
TI - Adenovirus-directed expression of dominant negative estrogen receptor induces apoptosis in breast cancer cells and regression of tumors in nude mice.
SO - Mol Med 2001 Nov;7(11):773-82
AD - Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611-2908, USA.
BACKGROUND: Estrogen receptors (ER) are expressed in about two thirds of human breast cancer, and are an important pharmacological target for treatment of these tumors. Dominant negative forms of the ER have been suggested as an alternative method to disrupt ER function. In this study, we examined the effect of dominant negative ER mutants (ER1-536 and L540Q) on ER-positive breast cancer cells in vitro and in vivo. MATERIALS AND METHODS: ER-positive T47D breast cancer cells were infected with adenoviral vectors expressing ER1-536 and L540Q to examine the effects of the mutants on gene expression and cell growth. Adenoviral vectors containing the wild type ER (AdwtER) and beta-galactosidase gene (AdGal) were used as controls. RESULTS: Ad1-536 or AdL540Q infection inhibited T47D cell growth and induced apoptosis, increasing Bax protein and phosphorylation of p38 mitogen-activated-protein kinase (MAPK). Consistent with the apoptotic effects in vitro, pre-infection of T47D cells with Ad1-536 or AdL540Q inhibited tumor formation when these cells were introduced into nude mice. In addition, injection of Ad1-536 and AdL540Q into pre-established T47D tumors induced tumor regression. Apoptosis, in conjunction with the activation of caspase-3 and phosphorylation of p38 MAPK, was detected in the shrinking tumors. Overexpression of wild-type ER by AdwtER infection also produced antiproliferative and apoptotic effects, but to a lesser extent than the ER1-536 and L540Q mutants. CONCLUSIONS: These results indicate that dominant negative ER mutants have the potential to induce apoptosis of T47D cells and regression of tumors. The delivery of dominant negative ERs by adenoviral vectors may provide a useful tool for targeted therapy of ER-positive breast cancer.
UI - 11792413
AU - Haase D; Binder C; Bunger J; Fonatsch C; Streubel B; Schnittger S;
TI - Griesinger F; Westphal G; Schoch C; Knopp A; Berkovicz D; Krieger O; Wormann B; Hilgers R; Hallier E; Schulz T Increased risk for therapy-associated hematologic malignancies in patients with carcinoma of the breast and combined homozygous gene deletions of glutathione transferases M1 and T1.
SO - Leuk Res 2002 Mar;26(3):249-54
AD - Department of Hematology and Oncology, Georg-August-University, Robert-Koch-Strasse 40, 37075 Gottingen, Germany. email@example.com
The most serious long-term complications of anti-tumor therapy are secondary malignancies. Parameters which might allow an estimation of the individual risk to develop a therapy-induced neoplasia are urgently needed. We examined whether the genotypes of the glutathione S-transferases (GST) M1 and T1, which metabolize various cytostatic drugs, as well as reactive oxygen species, influence the risk for secondary neoplasia. In a retrospective study, we analyzed peripheral blood lymphocyte or bone marrow DNA samples from 213 patients with acute myeloid leukemia (AML) and 128 with myelodysplastic syndromes (MDS) 44 of whom suffered from therapy-associated AML/MDS. The control group consisted of 239 healthy individuals with comparable composition as to race and sex. GSTM1 and GSTT1 were analyzed by multiplex PCR. Comparison between patients and control group revealed a significant (P=0.0003) overrepresentation of combined deletions of both GSTM1 and GSTT1 (double null genotype) in the group of patients with AML/MDS secondary to chemo- and/or radiotherapy of a carcinoma of the breast. In this group, 55% of the patients displayed the double null genotype as compared with 8.8% in the control group. We conclude that patients with carcinoma of the breast and inheritance of a combined gene deletion of GSTM1 and GSTT1 might bear an increased risk to develop a secondary therapy-induced hematologic neoplasia. An insufficient detoxification of cytostatic drugs such as cyclophosphamide is suggested to represent the underlying pathomechanism.
UI - 11933075
AU - Solanas M; Escrich E; Rouzaut A; Costa I; Martinez A; Notario V
TI - Deregulated expression of the PCPH proto-oncogene in rat mammary tumors induced with 7,12-dimethylbenz[a]anthracene.
SO - Mol Carcinog 2002 Apr;33(4):219-27
AD - Department of Cell Biology, Physiology, and Immunology, Universitat Autonoma de Barcelona, Spain.
The PCPH proto-oncogene was identified by its frequent activation in Syrian hamster fetal cells exposed to 3-methylcholanthrene. We previously isolated human PCPH cDNA and studied its expression in normal human tissues. We report herein the pattern of PCPH expression in normal rat tissues. Each tissue expressed one major PCPH polypeptide that varied in molecular mass in different tissues. Normal mammary gland expressed a single PCPH polypeptide of 27 kDa. This PCPH form also was expressed in lactating mammary glands but at significantly greater levels. These results suggest the existence of tissue-specific regulatory mechanisms for PCPH expression that may be influenced by the differentiation stage. Our previous studies on the involvement of PCPH in human cancer showed that human breast tumor cell lines have frequent alterations in PCPH, including multiple PCPH polypeptide forms that are not expressed in normal cells. These cell lines also have frequent loss of a 27-kDa form identified as the only PCPH polypeptide expressed by normal human breast epithelial cells. In this study, we found that these same alterations occurred in vivo during mammary carcinogenesis in Sprague-Dawley rats treated with 7,12-dimethylbenz[a]anthracene, in both benign and malignant tumors, indicating that stable changes in PCPH expression took place early in the neoplastic process. Results showed that this experimental system is relevant to human breast carcinogenesis and provides an excellent model to study the molecular basis of the regulation of PCPH expression during normal differentiation and pathologic stages of neoplasia of the mammary gland and to analyze the role of PCPH in the carcinogenic process. Furthermore, the detection of atypical PCPH polypeptides in tumors suggests that PCPH immunodetection may be applied as a diagnostic tool for the early identification of neoplastic breast epithelial cells. Copyright 2002 Wiley-Liss, Inc.
UI - 11859716
AU - Lai C; Jiang Z; Song S
TI - [Mutation BRCA1 gene in 186 breast cancer patients]
SO - Zhonghua Zhong Liu Za Zhi 2001 Nov;23(6):483-5
AD - Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100850, China.
OBJECTIVE: To analysis the mutation of BRCA1 gene in 186 breast cancer patients. METHODS: Polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) and sequential were used in this analysis. RESULTS: 13/186 of patients showed mutation which comprised 7% of the total number of patients. In 8 patients, the mutation was observed in the intron splicing region and in 5 patients, the mutation was on the exon. CONCLUSION: Mutation analysis of BRCA1 gene is helpful in the determination of developmental potential, early diagnosis and gene therapy for breast cancer.
UI - 11900572
AU - Bartley AN; Ross DW
TI - Validation of p53 immunohistochemistry as a prognostic factor in breast cancer in clinical practice.
SO - Arch Pathol Lab Med 2002 Apr;126(4):456-8
AD - Wake Forest University School of Medicine, Forsyth Medical Center, Winston-Salem, NC 27103, USA. firstname.lastname@example.org
CONTEXT: Abnormal p53 tumor suppressor gene expression as detected by immunohistochemistry is a possible prognostic factor in breast cancer. The difference in techniques used to evaluate the expression of mutated p53 protein is under intense scrutiny, as well as its uses either independently or in conjunction with other prognostic factors in breast cancer. OBJECTIVE: To determine whether p53 immunohistochemistry can be used as a reliable indicator of the presence of mutated nuclear p53 protein, and whether this method can be performed reliably in a community hospital's clinical practice. DESIGN: ne hundred twenty-two cases of breast carcinoma were stained and analyzed for the presence of p53 protein using DO-7 (Dako Corporation, Carpinteria, Calif) p53 antibody. RESULTS: Of the 122 cases of invasive carcinoma studied, 23 (18.7%) were positive for p53, and 16 (16.3%) of 98 cases with coexisting ductal carcinoma in situ were positive for p53. This finding is in agreement with comparable published studies. CONCLUSIONS: Based on the results of this study, we conclude that p53 immunohistochemistry qualifies as a diagnostic technique suitable for clinical practice in a community hospital. Its detection may be particularly promising in clinical trials of new molecular therapies directed at the p53 tumor suppressor gene.
UI - 11965543
AU - Billard LM; Magdinier F; Lenoir GM; Frappart L; Dante R
TI - MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland.
SO - Oncogene 2002 Apr 18;21(17):2704-12
AD - Laboratoire de Genetique, UMR 5641 CNRS, UCBL1, 8 avenue Rockefeller, 69373 Lyon cedex 08, France.
During the last years, a direct link between DNA methylation and repressive chromatin structure has been established. This structural modification is mediated by histone deacetylases targeted to the methylated sequences by Methyl Binding Proteins (MBD). Human cancer cells exhibit both a global hypomethylation and some localized hypermethylations suggesting that the deregulation of the methylation machinery is a central event in tumorigenesis. Therefore, we have investigated in human tissues the expression of two major MBDs, MeCP2 and MBD2, during the proliferation of normal breast and in benign and neoplasic breast tumors. Quantitation of the transcripts indicates that MBD2 mRNAs are 20-30-fold more abundant than MeCP2 transcripts in the adult and fetal human mammary gland. In pathological tissues samples MBD2 mRNA levels are significantly higher (P=0.001) in benign tumors compared with normal breast tissues, whereas MeCP2 expression is not modified in these specimens. In neoplasic samples a deregulation of the expression of both genes was found. The amounts of MBD2 and MeCP2 transcripts vary greatly between samples in cancer cells compared to normal breast tissues or benign tumors, and in invasive ductal carcinomas the amount of MBD2 mRNA is significantly (P=0.03) associated with the tumor size. Taken together these data suggest that upregulation of MBD2 might be associated with breast cell proliferation. In line with this hypothesis MBD2 is also upregulated during the prenatal development of the human mammary gland, but in contrast to that observed in tumor cells, MeCP2 is also coordinately upregulated in the fetal breast tissues, suggesting that deregulation of MeCP2 and MBD2 occurs in human breast cancers.
UI - 11975321
AU - Satge D; Sasco AJ; Pujol H; Rethore MO
TI - [Breast cancer in women with trisomy 21]
SO - Bull Acad Natl Med 2001;185(7):1239-52; discussion 1252-4
AD - Laboratoire d'Anatomie pathologique, Centre hospitalier, 19000 Tulle.
The population with Down's syndrome has a different cancer profile compared to the general population, even after taking into account issues of survival and ageing. Several solid tumours are unusually rare, whereas in contrast leukaemias are increased. In addition, few studies are available on this topic. We therefore decided to conduct a mortality study based on the INSERM national mortality statistics in France comparing over a 24 year period deaths from female breast cancer in the general French population with the cancer deaths in women with Down's syndrome. Only 5 deaths with Down's syndrome could be found compared to 68.98 expected based on national statistics. This clear reduction in risk agrees with other studies available in Down's syndrome patients. This observation could be partly explained by over expression of genes linked to gene dosage effects on chromosome 21, playing a role in cell growth, differentiation, survival and death. An additional protective effect could come from the marked and continued decreased exposure to oestrogens, starting in utero for women with trisomy 21 and lasting all over life.
UI - 11973868
AU - Nevanlinna H; Kallioniemi OP
TI - [Susceptibility genes of familiar breast cancer in Finland]
SO - Duodecim 1999;115(21):2365-74
AD - HYKS:n naistenklinikka, tutkimuslaboratorio PL 140, 00029 HYKS. email@example.com
UI - 11889595
AU - Bachelier R; Vincent A; Mathevet P; Magdinier F; Lenoir GM; Frappart L
TI - Retroviral transduction of splice variant Brca1-Delta11 or mutant Brca1-W1777Stop causes mouse epithelial mammary atypical duct hyperplasia.
SO - Virchows Arch 2002 Mar;440(3):261-6
AD - Laboratoire de genetique, UMR 5641 CNRS, Universite Claude Bernard Lyon I, Faculte de Medecine, 8 avenue Rockefeller, 69373 Lyon cedex 08, France.
We have investigated the effects of the expression of wild-type and mutant Brca1 alleles on the murine mammary gland morphogenesis and carcinogenesis. Primary cultures of mammary cells from BALB/cByJIco mice were infected with recombinant Babe Puro retroviruses expressing lacZ, full-length Brca1, splice variant Brca1-Delta11, or mutant Brca1-W1777Stop alleles. Infected cells were reinjected into the mammary fat pad of a syngeneic virgin mouse whose endogenous epithelium had previously been removed. Four months after reinjection, nulliparous and postlactating mice were checked for the reconstitution of the mammary gland. Stable expression of beta-galactosidase was observed in the ducts formed by epithelial mammary cells infected with Babe Puro/ lacZ retrovirus. Epithelial mammary cells transduced with full-length Brca1 developed normally, whereas those transduced with Brca1-Delta11 or Brca1-W1777Stop formed atypical duct hyperplasia associated with reduced branching. These results suggest that ectopically expressed splice variant Brca1-Delta11 and mutant Brca1-W1777Stop have dominant negative effects.
UI - 11996792
AU - Sommer SS; Buzin CH; Jung M; Zheng J; Liu Q; Jeong SJ; Moulds J; Nguyen
TI - VQ; Feng J; Bennett WP; Dritschilo A Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls.
SO - Cancer Genet Cytogenet 2002 Apr 1;134(1):25-32
AD - Department of Molecular Genetics, City of Hope National Medical Center, Duarte, CA 91010, USA. firstname.lastname@example.org
Studies of families of patients with ataxia telangiectasia (A-T) show an increased risk of breast cancer in heterozygous A-T carriers. However, expected increased levels of mutations in the ATM gene among unselected breast cancer patients have not been found to date. Previous methods of mutation detection were biased toward the detection of truncating mutations, and single nucleotide substitutions were likely to have been underreported. In this study, genomic DNA from 43 breast cancer patients and 43 control individuals were scanned for mutations in the entire ATM coding region (exons 4-65) and adjacent intronic splice regions (three megabases total) using detection of virtually all mutation-single-strand conformation polymorphism (SSCP), a modification of SSCP with sufficient redundancy to detect virtually all mutations. Excluding a polymorphism found commonly in cases and controls, there were missense changes in 12 breast cancer patients, one of whom also had a protein truncating mutation, versus six controls (P=0.09). When all structural changes common to the cases and controls were excluded, missense or truncating changes were found in 10 cases compared to two in controls (P=0.013). The background of missense changes in controls is high. There is a trend towards elevation of all structural changes in cases, but the results are not statistically significant. Cohort-specific structural changes are significantly more prevalent in the breast cancer patients. The data are compatible with certain missense mutations in ATM predisposing to breast cancer.
UI - 11935316
AU - Rozenblum E; Vahteristo P; Sandberg T; Bergthorsson JT; Syrjakoski K;
TI - Weaver D; Haraldsson K; Johannsdottir HK; Vehmanen P; Nigam S; Golberger N; Robbins C; Pak E; Dutra A; Gillander E; Stephan DA; Bailey-Wilson J; Juo SH; Kainu T; Arason A; Barkardottir RB; Nevanlinna H; Borg A; Kallioniemi OP A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes.
SO - Hum Genet 2002 Feb;110(2):111-21
AD - Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence we have assembled in silico an integrated 5.7-Mb genomic map with 90% sequence coverage. This area contains eight known genes, two hypothetical proteins, 24 additional Unigene clusters, and approximately 100 predicted genes and exons. We have determined the cDNA and genomic sequence, and tissue expression profiles for the KIAA1008 protein (homologous to the yeast mitotic control protein dis3+), KLF12 (AP-2 repressor), progesterone induced blocking factor 1, zinc finger transcription factor KLF5, and LIM domain only-7, and for the hypothetical proteins FLJ22624 and FLJ21869. Mutation screening of the five known genes in 19 breast cancer families has revealed numerous polymorphisms, but no deleterious mutations. These data provide a basis and resources for further analyses of this chromosomal region in the development of cancer.
UI - 11977534
AU - Miyoshi Y; Noguchi S
TI - [Genetic test and prophylactic treatment in breast cancer families]
SO - Gan To Kagaku Ryoho 2002 Apr;29(4):512-22
AD - Dept. of Surgical Oncology, Osaka University Graduate School of Medicine.
Fifteen (13.3%) and 21 (18.6%) deleterious germline mutations were identified in BRCA1, and BRCA2 genes among 113 Japanese breast cancer families. We found a BRCA1 codon 63 (nucleotide 307) nonsense mutation and a 4-bp deletion at codon 1858 (nucleotide 5802) of BRCA2 in 4 and 7 independent families, respectively. Haplotype analysis has revealed that these two mutations were founder mutations. Lifetime risk of breast cancer in BRCA1 or BRCA2 mutation carriers was estimated at nearly 80%, and that of ovarian cancer in BRCA1 mutation carriers was about 40%. A questionnaire survey as to the genetic testing (BRCA1 and BRCA2) and prevention was carried out with 146 healthy women (hospital workers or medical students) and 84 breast cancer patients. About 80% of healthy women as well as breast cancer patients responded positi