National Cancer Institute®
Last Modified: June 1, 2002
UI - 11777277
AU - Frank DH; Davis JR; Alberts DS; Thompson D; Liu Y; Bartels PH
TI - Nuclear chromatin characteristics of breast solid pattern ductal carcinoma in situ.
SO - Anal Quant Cytol Histol 2001 Dec;23(6):418-26
AD - Optical Sciences Center, University of Arizona, Tucson, USA.
OBJECTIVE: To characterize nuclei from breast solid pattern ductal carcinoma in situ (DCIS) by their karyometric features and to search for the presence of statistically significantly different subsets of nuclei. STUDY DESIGN: One hundred nuclei from each of 6 normal, 13 solid DCIS, (9 low and intermediate grade and 4 high grade DCIS) histopathologic samples of breast tissue were digitally recorded. Karyometric features were computed and subjected to a nonsupervised learning algorithm (P-index) to identify significantly different subgroups. RESULTS: Nuclei in low grade lesions displayed a diploid/near diploid pattern, while the majority of intermediate grade lesions fell into a range beyond 5N. The high grade lesions showed substantial genomic instability and represented three statistically different subsets or phenotypes. CONCLUSION: There is a progression of nuclear abnormality from low grade to high grade DCIS. The nuclei from high grade DCIS form a heterogeneous set that represents three phenotypes. One of these phenotypes shows a nuclear chromatin pattern that more closely resembles poorly differentiated, infiltrating disease. The observation of such a phenotype may have prognostic implications.
UI - 12025229
AU - Loveday RL; Speirs V; Drew PJ; Kerin MJ; Monson JR; Greenman J
TI - Intracellular flow cytometric analysis of primary cultured breast tumor cells.
SO - Cancer Invest 2002;20(3):340-7
AD - Department of Surgery, Medical Research Laboratory, Hull University, Cottingham Road, Hull, East Yorkshire HU6 7RX, UK.
Cell lines are traditionally used as tools for in vitro studies of breast cancer. It is highly debatable however, because of the genetic drift that occurs in such long term cultures how representative these cell lines are of breast cancer in vivo. For this reason primary cultures are generally regarded as a better model. Here we have used a primary culture technique (Int. J. Cancer, 66 (1996) 551; Br. J. Cancer, 78 (1998) 1421) to obtain primary breast cancer cells from 13 breast cancer biopsies. We then describe the development and use of methodology to confirm the purity of the cultures. The acquisition of a highly pure population of epithelial cells was confirmed by flow cytometric analysis of intracellular vimentin and cytokeratin 19. The methodology described will have many applications in studies requiring a highly pure population of epithelial breast cancer cells, as well as wide use in other cancers.
UI - 11714444
AU - Haga S; Emi M; Hirano A; Utada Y; Kajiwara T; Akiyama F; Sakamoto G;
TI - Takahashi K; Tada T; Kasumi F; Miki Y; Nakamura Y Association of allelic losses at 3p25.1, 13q12, or 17p13.3 with poor prognosis in breast cancers with lymph node metastasis.
SO - Jpn J Cancer Res 2001 Nov;92(11):1199-206
AD - Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Nakahara-ku, Kawasaki 211-8533.
To identify specific allelic losses that might correlate with postoperative mortality of patients with node-positive breast carcinomas, we examined tumors from a cohort of 263 such patients, who were followed clinically for 5 years postoperatively, for allelic losses among 18 microsatellite markers. Patients whose tumors had lost an allele at 3p25.1, 13q12, or 17p13.3 had significantly higher risks of mortality than those whose tumors retained both alleles at those loci. At 3p25.1, the 5-year mortality rate was 33.8% among patients with losses vs. 16.8% with retention (P = 0.0154); at 13q12, 30.3% vs. 13.0% (P = 0.0241); and at 17p13.3, 30.4% vs. 16.2% (P = 0.0243). Combined losses at 3p25.1 and 17p13.3 increased the predicted postoperative mortality risk by a factor of 4.9 (5-year mortality rate of 38.2% vs. 8.0%, P = 0.0006), and combined losses at 3p25.1 and 13q12 raised the predicted postoperative mortality risks by a factor of 2.9 (34.7% vs. 12.7%, P = 0.0441). These data indicate that loss of heterozygosity (LOH) at any one or a pair of loci at 3p25.1, 13q12, or 17p13.3 is a significant predictor of postoperative mortality for breast-cancer patients.
UI - 11857490
AU - Farabegoli F; Champeme MH; Bieche I; Santini D; Ceccarelli C; Derenzini
TI - M; Lidereau R Genetic pathways in the evolution of breast ductal carcinoma in situ.
SO - J Pathol 2002 Mar;196(3):280-6
AD - Department of Experimental Pathology, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy. email@example.com
The patterns of allelic loss in 28 cases of pure ductal carcinoma in situ (DCIS) and 25 cases of DCIS associated with invasive ductal carcinoma (IDC) were compared, in order to define whether pure DCIS represented an earlier stage than DCIS associated with IDC in the progression of breast carcinoma. To this aim, the polymerase chain reaction (PCR) was performed on microdissected normal and neoplastic breast tissue, formalin-fixed and paraffin-embedded. Fifteen microsatellite markers were examined, on chromosomes 1p, 3p, 7q, 11q, 12p, 13q, 16q and 17q, mostly focused on regions altered in breast cancer. Loss of heterozygosity (LOH) was greater in pure DCIS than in the DCIS component associated with IDC for 11 out of 15 markers. The difference was statistically significant for D13S260 and D17S800 (p=0.008 and p=0.01, respectively). DCIS associated with IDC showed a lesser degree of alteration than the synchronous IDC component for ten out of 15 markers. In contrast, LOH at D11S1816 and D16S318 was lower in pure DCIS than in DCIS associated with IDC and even greater in the IDC component. These results confirm that DCIS is a possible but not an obligate precursor of invasive breast cancer and suggest that pure DCIS and DCIS associated with IDC may be genetically distinct. The evolution from DCIS to IDC may follow multiple pathways and not a linear model. Copyright 2002 John Wiley & Sons, Ltd.
UI - 11857491
AU - Selim AG; Ryan A; El-Ayat G; Wells CA
TI - Loss of heterozygosity and allelic imbalance in apocrine metaplasia of the breast: microdissection microsatellite analysis.
SO - J Pathol 2002 Mar;196(3):287-91
AD - Department of Histopathology, St. Bartholomew's Hospital, St. Bartholomew's and the Royal London School of Medicine and Dentistry, University of London, West Smithfield, London EC1A 7BE, UK. firstname.lastname@example.org
Loss of heterozygosity (LOH) and allelic imbalance (AI) at loci reported to show allele loss and/or imbalance in preinvasive and invasive breast cancer were examined in 41 cases of apocrine metaplasia (APM) of the breast using a microdissection technique, polymorphic microsatellite markers, and the polymerase chain reaction (PCR). Occasional examples of LOH and/or AI were identified in 2/28 (7.1%) informative cases at 1p (MYCL1), 2/14 (14.3%) at 11q (INT2), 1/15 (6.7%) at 13q (D13S267), 3/22 (13.6%) at 16q (D16S539), 2/23 (8.7%) at 17p (TP53), and 1/11 (9.1%) at 17p (D17S513) and 3/16 (18.8%) at 17q (D17S250). The finding of LOH/AI in cases of APM indicates that a subset of APM appears clonal, but the significance of allelic loss or imbalance in the pathogenesis of APM or its possible subsequent progression to carcinoma is not yet clear and requires further investigation. Clinical follow-up of these particular cases of APM showing LOH/AI would be of further value. Copyright 2002 John Wiley & Sons, Ltd.
UI - 11889682
AU - Conto SI; Myers JS
TI - Risk factors and health promotion in families of patients with breast cancer.
SO - Clin J Oncol Nurs 2002 Mar-Apr;6(2):83-7
AD - email@example.com
Women with a family history of breast cancer have an increased risk of developing the disease. Women identified as "high risk" for developing breast cancer have been shown to exhibit increased levels of psychological distress and anxiety related to breast cancer. Oncology nurses can address this barrier and others, such as altered risk perception and lack of physician recommendation for screening. Oncology nurses also can identify high-risk families that may be candidates for genetic testing for breast cancer susceptibility, provide comprehensive teaching about breast self-examination (BSE), and clarify misconceptions about early detection. Primary prevention measures for hereditary breast cancer include prophylactic mastectomy and oophorectomy and chemopreventative agents. Secondary prevention measures include screening and early detection with mammography, clinical breast examinations, and BSE. Nurses have a responsibility to educate families of patients with breast cancer about risk factors, primary and secondary preventive measures, genetic testing, and screening recommendations.
UI - 11986781
AU - Chang A; Yousef GM; Scorilas A; Grass L; Sismondi P; Ponzone R;
TI - Diamandis EP Human kallikrein gene 13 (KLK13) expression by quantitative RT-PCR: an independent indicator of favourable prognosis in breast cancer.
SO - Br J Cancer 2002 May 6;86(9):1457-64
AD - Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Kallikreins are a group of serine proteases with diverse physiological functions. KLK13 (previously known as KLK-L4) is a novel kallikrein gene located on chromosome 19q13.4 and shares a high degree of homology with other kallikrein family members. Many kallikrein genes were found to be differentially expressed in various malignancies, and their regulation is controlled by steroid hormones in prostate and breast cancer cell lines. We studied the expression of KLK13 by quantitative reverse transcriptase-polymerase chain reaction in 173 patients with epithelial breast carcinoma. An optimal cutoff point equal to the 40th percentile was defined, based on the ability of KLK13 to predict disease-free survival. KLK13 values were then associated with other established prognostic factors and with disease-free survival and overall survival. Higher positivity for KLK13 expression was found in older, oestrogen receptor positive patients. In univariate analysis, KLK13 expression is a significant predictor of improved disease-free survival and overall survival (P<0.001 and P=0.009, respectively). Cox multivariate analysis indicated that KLK13 was an independent prognostic variable in the subgroups of patients with Grade I-II tumours and in patients who were oestrogen receptor and progesterone receptor positive, and node positive. Hazard ratios derived from Cox analysis, related to disease-free survival and overall survival were 0.22 (P=0.001) and 0.24 (P=0.008), respectively, for the Grade I-II group; 0.36 (P=0.008) and 0.44 (P=0.038), respectively, for the node positive group and 0.36 (P=0.008) and 0.18 (P=0.008), respectively, for the oestrogen receptor positive group. The adjusted hazard ratio for progesterone receptor positive patients for disease-free survival was 0.25 (P=0.012). For patients in the node positive and oestrogen receptor positive subgroup (n=51) the adjusted hazard ratio was 0.25 (P=0.006) and for the node positive and progesterone receptor positive subgroup (n=46) the hazard ratio was 0.24 (P=0.008). Taken together, these data suggest that higher KLK13 expression in these subgroups of breast cancer patients is associated with an approximately 55 to 80% reduction in the risk of relapse or death. We conclude that KLK13 expression, as assessed by quantitative reverse transcriptase-polymerase chain reaction, is an independent favourable prognostic marker for breast carcinoma. Copyright 2002 Cancer Research UK
UI - 11759829
AU - Powell BL; Bydder S; Grieu F; Gnanasampanthan G; Elsaleh H; Seshadri R;
TI - Berns EM; Iacopetta B Prognostic value of TP53 gene mutation in adjuvant treated breast cancer patients.
SO - Breast Cancer Res Treat 2001 Sep;69(1):65-8
AD - Department of Surgery, University of Western Australia, Nedlands, Australia.
We investigated the prognostic significance of mutation to the TP53 tumor suppressor gene in a series of 908 breast cancer patients treated with or without adjuvant therapies. The frequency of TP53 mutation detected by single strand conformation polymorphism (SSCP) was 19.4% (176/908) in the overall tumor series. In multivariate analysis, TP53 mutation was independently associated with worse survival in the overall (HR = 2.1, 95% CI [1.5-3.1], P<0.0001), non-adjuvant treated (HR=2.2, 95% CI [1.2-4.2], P=0.017) and adjuvant treated (HR= 2.0, 95% CI [1.3-3.1], P = 0.0009) patients.
UI - 11858293
AU - Zimmerman VL; Smeltzer SC
TI - Hormone therapy and breast cancer.
SO - Clin Excell Nurse Pract 2000 Jan;4(1):30-4
AD - Health Promotion for Women with Disabilities Project, College of Nursing, Villanova University, Pennsylvania 19085, USA. Vanessa.firstname.lastname@example.org
Use or nonuse of hormone therapy (HT) is a controversial decision for menopausal women that has taken on increasing significance as the large number of baby boomers enter this life stage. Studies suggest benefits of HT for prevention of osteoporosis and coronary artery disease, as well as a possible increased risk for cancer, particularly breast cancer. Because of this risk for breast cancer, women with a family history may feel differently about HT. However, differences have not been studied. The purpose of this study was to examine differences in attitudes toward HT of menopausal women with and without a family history of breast cancer. A nonexperimental, cross-sectional design was used. The setting included various sites located in a rural community in northwestern Pennsylvania. A convenience sample of 110 was obtained. A Health Belief Model attitudinal scale was completed by the participants. Although there were no significant differences in attitudes toward HT between the groups, ancillary analysis revealed a significant difference (P = .04) in frequency of reported fear of breast cancer regarding HT in those women with a family history of breast cancer and those without such a history. The findings of this study point to a need for further research on attitudes of women regarding HT and how they may affect postmenopausal healthcare management.
UI - 11911250
AU - Evtimova V; Schwirzke M; Tarbe N; Burtscher H; Jarsch M; Kaul S; Weidle
TI - UH Identification of breast cancer metastasis-associated genes by chip technology.
SO - Anticancer Res 2001 Nov-Dec;21(6A):3799-806
AD - Roche Diagnostics GmbH, Division Pharma, Penzberg, Germany.
In order to identify genes associated with metastasis of mammary carcinoma, we compared the transcriptional profile (Affymetrix chip technology) of two cell lines derived from primary mammary carcinoma, three cell lines derived from bone marrow micrometastasis, a cell line derived from a lymph node metastasis as well as a cell line derived from malignant ascites. We found that 11 genes (0.16%) were up-regulated in all five cell lines derived from metastasis and 32 genes (0.45%) were up-regulated in four of these cell lines. Sixteen genes (0.23%) were down-regulated in the five metastatic cell lines, while 24 genes (0.34%) were down-regulated in four of the metastatic cell lines. The usefulness of our system for the identification of genes associated with metastasis of mammary carcinoma is demonstrated by the identification of genes which have already been implicated in metastasis of mammary carcinoma. This suggests that further evaluation of identified de-regulated genes, which until now have not been seen in context with metastasis of mammary carcinoma, should be undertaken.
UI - 11979433
AU - Papadopoulos S; Benter T; Anastassiou G; Pape M; Gerhard S; Bornfeld N;
TI - Ludwig WD; Dorken B Assessment of genomic instability in breast cancer and uveal melanoma by random amplified polymorphic DNA analysis.
SO - Int J Cancer 2002 May 10;99(2):193-200
AD - Department of Obstetrics and Gynecology, Free University of Berlin, Berlin, Germany.
Some types of cancer have been associated with abnormal DNA fingerprinting. We used random amplified polymorphic DNA (RAPD) to generate fingerprints that detect genomic alterations in human breast cancer. Primers were designed by choosing sequences involved in the development of DNA mutations. Seventeen primers in 44 different combinations were used to screen a total of 6 breast cancer DNA/normal DNA pairs and 6 uveal melanoma DNA/normal DNA pairs. Forty-five percent of these combinations reliably detected quantitative differences in the breast cancer pairs, while only 18% of these combinations detected differences in the uveal melanoma pairs. Fourteen (32%) and 12 (27%) primers generated a smear or did not produce any band patterns in the first and second cases, respectively. Taking into account the ability of RAPD to screen the whole genome, our results suggest that the genomic damage in breast cancer is significantly higher than in uveal melanoma. Our study confirms other reports that the molecular karyotypes produced with random priming, called amplotypes, are very useful for assessing genomic damage in cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 11979449
AU - Osorio A; de la Hoya M; Rodriguez-Lopez R; Martinez-Ramirez A; Cazorla
TI - A; Granizo JJ; Esteller M; Rivas C; Caldes T; Benitez J Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer.
SO - Int J Cancer 2002 May 10;99(2):305-9
AD - Department of Human Genetics, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain. email@example.com
The BRCA1 and BRCA2 genes are responsible for a high proportion of familial breast cancer; germline mutations in these genes confer a lifetime risk of about 70% for developing breast cancer. Most of the described deleterious mutations are small deletions or insertions that originate a truncated protein; however, in many cases, they are amino acid changes whose significance is unknown. In these cases, there are some tests that can analyze the meaning of these variants, but most remain unclassified. The BRCA genes are tumor suppressors and it is believed that complete loss of the wild-type allele is a common mechanism of inactivation in tumors from patients carrying a germline deleterious mutation in these genes; if this is true, loss of heterozygosity (LOH) analysis in the tumor sample could help to distinguish if a rare variant is either a deleterious mutation or a common polymorphism. In the present study, we performed LOH analysis at the BRCA loci in 47 tumors from patients who belonged to high-risk breast cancer families and were carriers of any type of alteration in these genes. Our results suggest that (i) loss of the wild-type allele is the most common mechanism of inactivation in tumors from patients who carry a deleterious mutation in any of the genes, (ii) this loss is not common when we analyze familial tumors not associated with mutations in BRCA and (iii) LOH can be used to clarify variants of unknown significance in the BRCA genes. Copyright 2002 Wiley-Liss, Inc.
UI - 12010857
AU - Spurdle AB; Hopper JL; Chen X; McCredie MR; Giles GG; Venter DJ; Southey
TI - MC; Chenevix-Trench G The progesterone receptor exon 4 Val660Leu G/T polymorphism and risk of breast cancer in Australian women.
SO - Cancer Epidemiol Biomarkers Prev 2002 May;11(5):439-43
AD - Oncology Division, Joint Experimental Oncology Programme, The Queensland Institute of Medical Research, and The University of Queensland, Brisbane, 4029, Australia. mandyS@qimr.edu.au
An Alu insertion polymorphism of the progesterone receptor (PR) wasreported recently to be associated with a reduced risk of breast cancer, with risks of 0.8- and 0.3-fold associated with the heterozygote and homozygote genotypes, respectively. This intronic variant is considered to be in linkage disequilibrium with an exon 4 hinge region G to T Val660Leu polymorphism. We investigated whether the exon 4 PR polymorphism was associated with breast cancer in Australian women, using a population-based study of 1452 cases and 793 controls, half of whom were <40 years of age, and the other half were 40-59 years of age. There was no difference in genotype distribution between cases and controls (P = 0.5) and no evidence of risk associated with either the GT or TT genotypes compared with the common GG genotype. The adjusted odds ratios (ORs) were 0.97 (95% confidence interval, 0.79-1.19) and 1.52 (95% confidence interval, 0.87-2.66), respectively (P = 0.8 and 0.1), and the results were independent of age and family history of breast cancer. Our data provided no support for the previously reported decreased risk of breast cancer associated with the T allele, with 80% power to detect an OR of 0.8 or less for the heterozygote genotype and 90% power to detect an OR of 0.3 or less for the rare homozygous TT genotype. There was also no support for a greatly increased risk of breast cancer associated with the T allele, given that we had 80% power to detect risks of 1.3 and 2.0 associated with the GT and TT genotypes, respectively. We therefore conclude that this polymorphism is not associated with a markedly reduced or increased risk of breast cancer in Australian women <60 years of age. However, despite its considerable size, our study cannot exclude a small reduced or increased risk associated with the T allele, especially the rare TT genotype.
UI - 12010864
AU - De Vivo I; Hankinson SE; Li L; Colditz GA; Hunter DJ
TI - Association of CYP1B1 polymorphisms and breast cancer risk.
SO - Cancer Epidemiol Biomarkers Prev 2002 May;11(5):489-92
AD - Department of Epidemiology, Harvard Center for Cancer Prevention, Harvard School of Public Health, and the Channing Laboratory, Boston, Massachusetts 02115, USA. Devivo@channing.harvard.edu
Cytochrome P450 1B1 catalyzes the conversion of 17-beta-estradiol (E2) to thecatechol estrogen metabolites 2-OH-E2 and 4-OH-E2 that have been postulated to be involved in mammary carcinogenesis. We sought to determine whether two common functional polymorphisms in Cytochrome P450 1B1, V432L (m1), and A453S (m2) are related to breast cancer risk. Using a nested case control design within the Nurses' Health Study cohort, we genotyped 453 cases and 456 controls and found no significant association between m1[val/leu and leu/leu versus val/val, OR = 1 (CI, 0.72-1.45)] or m2 [asn/ser and ser/ser versus asn/asn, OR = 0.8 (CI, 0.62-1.15)] and breast cancer risk. However, we did observe women with the Val/Val (m1) genotype to have a higher percentage of estrogen receptor-positive tumors (P = 0.03). We did not observe any correlation with the m2 genotypes and estrogen receptor status. The association of the m1 and m2 genotypes on plasma hormone levels in postmenopausal control women not using hormone replacement therapy was also evaluated. Carriers of the m1 leu and m2 ser alleles had modestly higher estradiol levels but similar estrone and estrone sulfate levels. The results presented do not support a strong association between m1 and m2 and the risk of breast cancer.
UI - 12034524
AU - Ojopi EP; Cavalli LR; Cavalieri LM; Squire JA; Rogatto SR
TI - Comparative genomic hybridization analysis of benign and invasive male breast neoplasms.
SO - Cancer Genet Cytogenet 2002 Apr 15;134(2):123-6
AD - Department of Genetics, IB-UNESP, Botucatu, Sao Paulo, Brazil.
Comparative genomic hybridization (CGH) analysis was performed for the identification of chromosomal imbalances in two benign gynecomastias and one malignant breast carcinoma derived from patients with male breast disease and compared with cytogenetic analysis in two of the three cases. CGH analysis demonstrated overrepresentation of 8q in all three cases. One case of gynecomastia presented gain of 1p34.3 through pter, 11p14 through q12, and 17p11.2 through qter, and loss of 1q41 through qter and 4q33 through qter. The other gynecomastia presented del(1)(q41) as detected by both cytogenetic and CGH analysis. CGH analysis of the invasive ductal carcinoma confirmed a gain of 17p11.2 through qter previously detected by cytogenetic analysis. These regions showed some similarity in their pattern of imbalance to the chromosomal alterations described in female and male breast cancer.
UI - 12034525
AU - Nakopoulou L; Tsirmpa I; Giannopoulou I; Trafalis D; Katsarou S; Davaris
TI - P Aneuploidy of chromosome 20 in invasive breast cancer correlates with poor outcome.
SO - Cancer Genet Cytogenet 2002 Apr 15;134(2):127-32
AD - Department of Pathology, Medical School, The National and Kapodistrian University of Athens, Greece. firstname.lastname@example.org
Breast carcinoma is a genetically and phenotypically heterogeneous disease and is frequently associated with nonrandom chromosomal alterations. The aim of this study was to investigate the numerical aberrations of chromosome 20 in breast cancer. The observed chromosome-specific numerical abnormalities were evaluated along with the established clinicopathological parameters, the immunohistochemical expression of ER, PR, p53, c-erbB-2, Ki-67 and patients' survival. Nonisotopic in situ hybridization was applied to interphase cell nuclei on paraffin embedded tissue sections. Polysomy of chromosome 20 was the prevalent alteration in 45 of 50 (90%), monosomy in 2 of 50 (4%) and disomy in 3 of 50 (6%) cases. Invasive ductal carcinomas displayed a higher percentage of polysomy than lobular ones. A statistical significant association was demonstrated between Ki-67 immunohistochemical expression and polysomy of chromosome 20. Disomy was inversely correlated with Ki-67, while monosomy was suggestively associated with PR positive expression. Among the patients, those with the highest levels of polysomy showed the worst survival. In conclusion, the gain of chromosome 20 is the prevalent aberration in patients with breast carcinomas and may be useful prognostic marker in breast cancer.
UI - 12013533
AU - Debies MT; Welch DR
TI - Genetic basis of human breast cancer metastasis.
SO - J Mammary Gland Biol Neoplasia 2001 Oct;6(4):441-51
AD - Jake Gittlen Cancer Research Institute, College of Medicine, Penn State University, Hershey 17033-0850, USA.
Once cancer cells have spread and formed secondary masses, breast cancers are largely incurable even with state-of-the-art medicine. To improve diagnosis and therapy, better markers are needed to distinguish cells which have a high probability for causing clinically relevant, macroscopic metastases. In this review, we summarize the several genes that regulate breast cancer metastasis. Two categories of genes are presented--metastasis activator (ras, MEK1, mta1, proteinases, adhesion molecules, chemoattractants/receptors, autotaxin, PKC, S100A4, RhoC, osteopontin) and metastasis suppressor (Nm23, E-cadherin, TIMPs, KiSS1, Kai1, Maspin, MKK4, BRMS1). While the mechanisms of action for most of these genes are not fully elucidated, some clues are emerging and are presented.
UI - 12013534
AU - Foulkes WD; Rosenblatt J; Chappuis PO
TI - The contribution of inherited factors to the clinicopathological features and behavior of breast cancer.
SO - J Mammary Gland Biol Neoplasia 2001 Oct;6(4):453-65
AD - Department of Oncology, McGill University, Montreal, Quebec, Canada. email@example.com
This review is focused on genetic factors that may influence the development and/or appearance of breast cancer metastases. Over the last decade there have been significant advances in the understanding of genetic predisposition to breast cancer. The first breast cancer predisposing gene to be identified was TP53, and this was followed over the next 5 years by two more genes, BRCA1 and BRCA2, which from a population perspective are much more important than TP53. Other rarer genes have subsequently been identified, but the role of more common, less penetrant genes in breast cancer susceptibility remains unknown. Recent work has shown that breast cancers occurring in women carrying germ-line BRCA1 mutations tend to have clinicopathological features that are usually associated with a poor prognosis, such as high grade, estrogen receptor negative status and somatic TP53 mutations. On the other hand, they are usually ERBB2 negative. Whether or not such tumors are more or less likely to metastasize, and hence be associated with a poor outcome, is currently uncertain and has been the subject of much debate. Here, we outline some of the clinicopathological features of hereditary breast cancer, discuss the prognostic studies that have been performed, and introduce some possible new research directions.
UI - 11992555
AU - Geoffroy-Perez B; Janin N; Ossian K; Lauge A; Stoppa-Lyonnet D; Andrieu
TI - N Variation in breast cancer risk of heterozygotes for ataxia-telangiectasia according to environmental factors.
SO - Int J Cancer 2002 Jun 1;99(4):619-23
AD - Inserm EMI00-06, Tour Evry 2, 523 Place des Terrasses d l'Agora, 91034 Evry Cedex, France.
Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder, characterized by progressive neuronal degeneration, immunological deficiency, radio-sensitivity and an increased risk of cancer. Although several studies have confirmed that AT heterozygosis increases the risk of breast cancer (BC), we do not know how exogenous factors affect this risk. We performed an epidemiological study on the cancer risks associated with AT heterozygosis in France and explored the variation in BC risk according to environmental factors, such as reproductive factors and exposure to ionizing radiation. Information on the amount of ionizing radiation received by an individual in their lifetime and on their reproductive life was collected from the living relatives of 34 AT children (175 female relatives). Consistent with previous reports and with our previous estimate on the entire retrospective cohort, we found that the risk of developing BC is 3.6-fold higher among ATM heterozygous women. An increased risk was associated with an early age at menarche, a late age at first childbirth, nulliparity, premenopausal status and increasing periods of breast cell mitotic activity (BCMA) prior to the first childbirth. Age at menarche, age at 1st childbirth and BCMA seemed to have a stronger effect in ATM heterozygotes than in non-ATM heterozygotes. However, the tests were not all statistically significant (only age at 1st childbirth). Surprisingly, the risk of BC decreased when the chest or breasts were irradiated. It is difficult to interpret the data because of the small sample size, but further investigations should provide a biological explanation for the variation in BC risk associated with exogenous factors according to ATM heterozygosis status. Copyright 2002 Wiley-Liss, Inc.
UI - 12011455
AU - Desai KV; Xiao N; Wang W; Gangi L; Greene J; Powell JI; Dickson R; Furth
TI - P; Hunter K; Kucherlapati R; Simon R; Liu ET; Green JE Initiating oncogenic event determines gene-expression patterns of human breast cancer models.
SO - Proc Natl Acad Sci U S A 2002 May 14;99(10):6967-72
AD - Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA.
Molecular expression profiling of tumors initiated by transgenic overexpression of c-myc, c-neu, c-ha-ras, polyoma middle T antigen (PyMT) or simian virus 40 T/t antigen (T-ag) targeted to the mouse mammary gland have identified both common and oncogene-specific events associated with tumor formation and progression. The tumors shared great similarities in their gene-expression profiles as compared with the normal mammary gland with an induction of cell-cycle regulators, metabolic regulators, zinc finger proteins, and protein tyrosine phosphatases, along with the suppression of some protein tyrosine kinases. Selection and hierarchical clustering of the most variant genes, however, resulted in separating the mouse models into three groups with distinct oncogene-specific patterns of gene expression. Such an identification of targets specified by particular oncogenes may facilitate development of lesion-specific therapeutics and preclinical testing. Moreover, similarities in gene expression between human breast cancers and the mouse models have been identified, thus providing an important component for the validation of transgenic mammary cancer models.
UI - 12011458
AU - Bera TK; Iavarone C; Kumar V; Lee S; Lee B; Pastan I
TI - MRP9, an unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer.
SO - Proc Natl Acad Sci U S A 2002 May 14;99(10):6997-7002
AD - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4264, USA.
Combining a computer-based screening strategy and functional genomics, we previously identified MRP9 (ABCC12), a member of the ATP-binding cassette (ABC) superfamily. We now show that the gene has two major transcripts of 4.5 and 1.3 kb. In breast cancer, normal breast, and testis, the MRP9 gene transcript is 4.5 kb in size and encodes a 100-kDa protein. The protein is predicted to have 8 instead of 12 membrane-spanning regions. When compared with closely related ABC family members, it lacks transmembrane domains 3, 4, 11, and 12 and the second nucleotide-binding domain. In other tissues including brain, skeletal muscle, and ovary, the transcript size is 1.3 kb. This smaller transcript encodes a nucleotide-binding protein of approximately 25 kDa in size. An in situ hybridization study shows that the 4.5-kb transcript is expressed in the epithelial cells of breast cancer. An antipeptide antibody designed to react with the amino terminus of the protein detects a 100-kDa protein in testis and the membrane fraction of a breast cancer cell line. Because the 4.5-kb RNA is highly expressed in breast cancer and not expressed at detectable levels in essential normal tissues, MRP9 could be a useful target for the immunotherapy of breast cancer. Because of the unusual topology of the two variants of MRP9, we speculate that they may have a different function from other family members.
UI - 11481359
AU - Warner E; Plewes DB; Shumak RS; Catzavelos GC; Di Prospero LS; Yaffe MJ;
TI - Goel V; Ramsay E; Chart PL; Cole DE; Taylor GA; Cutrara M; Samuels TH; Murphy JP; Murphy JM; Narod SA Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer.
SO - J Clin Oncol 2001 Aug 1;19(15):3524-31
AD - Division of Medical Oncology, Department of Medical Biophysics, and Centre for Research in Women's Health, Toronto, Ontario, Canada. firstname.lastname@example.org
PURPOSE: Recommended surveillance for BRCA1 and BRCA2 mutation carriers includes regular mammography and clinical breast examination, although the effectiveness of these screening techniques in mutation carriers has not been established. The purpose of the present study was to compare breast magnetic resonance imaging (MRI) with ultrasound, mammography, and physical examination in women at high risk for hereditary breast cancer. PATIENTS AND METHODS: A total of 196 women, aged 26 to 59 years, with proven BRCA1 or BRCA2 mutations or strong family histories of breast or ovarian cancer underwent mammography, ultrasound, MRI, and clinical breast examination on a single day. A biopsy was performed when any of the four investigations was judged to be suspicious for malignancy. RESULTS: Six invasive breast cancers and one noninvasive breast cancer were detected among the 196 high-risk women. Five of the invasive cancers occurred in mutation carriers, and the sixth occurred in a woman with a previous history of breast cancer. The prevalence of invasive or noninvasive breast cancer in the 96 mutation carriers was 6.2%. All six invasive cancers were detected by MRI, all were 1.0 cm or less in diameter, and all were node-negative. In contrast, only three invasive cancers were detected by ultrasound, two by mammography, and two by physical examination. The addition of MRI to the more commonly available triad of mammography, ultrasound, and breast examination identified two additional invasive breast cancers that would otherwise have been missed. CONCLUSION: Breast MRI may be superior to mammography and ultrasound for the screening of women at high risk for hereditary breast cancer.
UI - 11789566
AU - Umemura S; Iwasaka T; Kakimoto K; Takahashi A; Koizumi H; Miyakawa Y;
TI - Kurotani R; Osamura RY Expression of prolactin gene in spontaneous mammary tumors in aging Fischer 344 rats.
SO - Endocr J 2001 Oct;48(5):597-602
AD - Department of Pathology, Tokai University School of Medicine, Isehara, Japan.
Expression of extra pituitary prolactin (PRL) has been recently reported in the mammary gland. However, spontaneous mammary tumors occurring in aging rats have not been investigated for PRL production. The present study was undertaken to examine the expression of PRL gene in rat mammary tumors spontaneously arisen in rats with pituitary prolactinomas among 130 female Fischer-344 (F-344) rats. The tumors examined were fibroadenoma (adenomatous type) in the 18-month old rat and adenocarcinoma (alveolar/tubular type) in the 21-month old rat. PRL mRNA was examined by solution and in situ reverse transcription-polymerase chain reaction (RT-PCR) method. The predicted amplified products for PRL mRNA were identified in both tumors, and its expression was confirmed to be in the cytoplasm of epithelial cells. The results of the present study showed that PRL gene is expressed in spontaneously arising mammary tumors.
UI - 11992405
AU - Autiero M; Camarca A; Ciullo M; Debily MA; El Marhomy S; Pasquinelli R;
TI - Capasso I; D'Aiuto G; Anzisi AM; Piatier-Tonneau D; Guardiola J Intragenic amplification and formation of extrachromosomal small circular DNA molecules from the PIP gene on chromosome 7 in primary breast carcinomas.
SO - Int J Cancer 2002 May 20;99(3):370-7
AD - Genetique Moleculaire et Biologie du Developpement, Centre National de la Recherche Scientifique, Villejuif, France.
The PIP gene is expressed in exocrine glands and, in pathologic conditions, in breast cysts and breast cancers exhibiting apocrine features. It is localized on the long arm of chromosome 7, a region frequently alterated in mammary tumors. We previously described an abnormal restriction pattern of the PIP gene in 33% of prostate carcinomas analyzed. Here, we analyze the structure of the PIP gene in primary breast carcinomas. We report that part of the 3' end, including exon 3, intron C, two-thirds of exon 4 and a small portion of intron B, is amplified and involved in the formation of extrachromosomal spcDNA molecules in 3/14 (21.4%) breast cancers analyzed. The involvement of a well-defined intragenic region of a gene in the formation of spcDNA appears to be unprecedented. Since spcDNA has been suggested to serve as an enhancer of genetic instability, the PIP gene may be the target of genomic variability processes in breast cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 11992413
AU - Russo A; Herd-Smith A; Gestri D; Bianchi S; Vezzosi V; Rosselli Del
TI - Turco M; Cardona G Does family history influence survival in breast cancer cases?
SO - Int J Cancer 2002 May 20;99(3):427-30
AD - Epidemiology Unit, Local Health Authority of Milan, Milan, Italy. RUSSAOG@TISCALI.IT
A few studies have suggested a relatively better prognosis for breast cancer (BC) cases reporting a positive family history (FH). We aimed at comparing the survival of patients according to FH in a large hospital-based series of 1,278 BC cases. Information on FH for BC was obtained at diagnosis by interview. All cases reporting a first- or second-degree FH for breast carcinoma were compared with cases without FH. Overall survival was estimated using a product-limit method. Hazard ratios (HRs) and the corresponding 95% confidence intervals (95% CIs), adjusted for confounding factors, were computed using proportional hazard models. Overall, 240 (18.8%) cases reporting, at diagnosis, a positive FH (156 with at least 1 first-degree relative and 84 with at least 1 second-degree relative) were compared with 1,038 patients without FH for BC. No significant differences were found in terms of distribution of age at diagnosis, tumor stage, nodal involvement, receptor status and histology. Cumulative survival rates at 5 years for cases without FH and with first-degree and second-degree FH for BC were 79.8 (95% CI 77.0-83.0), 78.6 (95% CI 70.0-88.0) and 80.2 (95% CI 68.0-92.0), respectively (log-rank test, chi(2) (2) = 0.02, p = 1.0). After adjustment for age, pathologic size and nodal involvement, the HR among cases of invasive cancer with a first-degree FH of BC was 0.91 (95% CI 0.55-1.48); however, the HR for cases with second-degree FH was 1.18 (95% CI 0.62-2.25) compared to cases without FH. Our study, based on a large series of consecutive invasive BC cases, did not find any significant survival differences associated with a positive FH for breast carcinoma, suggesting the existence of a large heterogeneity among BC cases with FH. Copyright 2002 Wiley-Liss, Inc.
UI - 12039933
AU - Berry DA; Iversen ES Jr; Gudbjartsson DF; Hiller EH; Garber JE; Peshkin
TI - BN; Lerman C; Watson P; Lynch HT; Hilsenbeck SG; Rubinstein WS; Hughes KS; Parmigiani G BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
SO - J Clin Oncol 2002 Jun 1;20(11):2701-12
AD - Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA. email@example.com
PURPOSE: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. PATIENTS AND METHODS: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. RESULTS: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. CONCLUSION: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.
UI - 12047143
AU - Hoff ER; Tubbs RR; Myles JL; Procop GW
TI - HER2/neu amplification in breast cancer: stratification by tumor type and grade.
SO - Am J Clin Pathol 2002 Jun;117(6):916-21
AD - Department of Anatomic Pathology, Cleveland Clinic Foundation, OH 44195, USA.
The presence of HER2/neu gene amplification is prognostically and therapeutically significant for patients with breast cancer. We sought to determine whether a relationship exists between HER2/neu gene amplification and the histologic type and grade of tumor. The histologic features and corresponding HER2/neu amplification results of 401 cases of invasive breast carcinoma were reviewed. Lobular carcinomas were less likely than ductal carcinomas to have HER2/neu amplification. Amplification was less frequent in Scarff-Bloom-Richardson grade I ductal carcinomas than in grades 2 and 3. Metastatic carcinomas frequently displayed HER2/neu amplification (6/20 [30%]). Our results support a correlation between HER2/neu amplification and the histologic type and grade of breast cancer. We suggest reexamination of tumors diagnosed as Scarff-Bloom-Richardson grade I invasive ductal carcinomas or lobular carcinomas if the lesion displays HER2/neu amplification to assure the exclusion of a higher grade of lesion or of missed ductal components.
UI - 12047146
AU - McCormick SR; Lillemoe TJ; Beneke J; Schrauth J; Reinartz J
TI - HER2 assessment by immunohistochemical analysis and fluorescence in situ hybridization: comparison of HercepTest and PathVysion commercial assays.
SO - Am J Clin Pathol 2002 Jun;117(6):935-43
AD - Department of Pathology and the United Hospital Breast Center, United Hospital, St Paul, MN 55102, USA.
We determined HER2 protein overe