Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two families with autosomal dominantly inherited desmoid tumors have recently been shown to have germline mutations at the 3' end of the APC gene. We subsequently identified an Amish family with autosomal dominantly inherited desmoid tumors. Genetic analysis performed on one family member, a 47-year-old man with multiple desmoid tumors and no colon polyps, revealed a protein truncating mutation in the middle of the APC gene. The truncating mutation is the result of a 337-bp insertion of an Alu I sequence into codon 1526 of the APC gene. The presence of a poly(A) tail at the 3' end of the insertion suggests that the Alu I sequence was inserted by a retrotranspositional event. Germline insertions of Alu I sequences have occasionally been reported to cause other genetic diseases including type I neurofibromatosis, hereditary site-specific breast cancer (BRCA2), and hemophilia B. However, this is the first report of a germline mutation of the APC gene resulting from an Alu I insertion.
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PMID:Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene. 1007 30

MYC gene overexpression was identified recently as a downstream step at the end of the Wnt/APC/beta-catenin pathway dysregulation observed in colorectal cancer (T-C. He et al., Science (Washington DC), 281: 1509-1512, 1998). It thus appears that an excess of c-myc protein is a primary cause of numerous cancers. In breast cancer, MYC has been studied mostly at the DNA level because of the poor quality of available antibodies against the protein product. The renewed interest in MYC calls for a sensitive and accurate method for analyzing MYC overexpression in breast tumors. We have developed a real-time quantitative reverse transcription-PCR assay based on TaqMan fluorescence methodology to quantify the MYC mRNA copy number. We validated the method on a large series of breast tumors. MYC gene overexpression was observed in 29 of 134 (22%) breast tumor RNAs, ranging from 3.2 to 19 times the level in normal breast tissues. These data imply that dysregulated MYC gene expression is potentially involved in the pathogenesis of breast cancer, especially by favoring local cell proliferation. We also found that MYC gene overexpression was rarely due to an increased MYC gene copy number in breast cancer. This new, simple, rapid, and semiautomated method will be useful for screening cancer patients for MYC overexpression and will prove a powerful tool in large, randomized, prospective, cooperative group trials and in the MYC-based therapy project.
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PMID:Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay. 1038 26

The I1307K polymorphism in APC has been found to predispose to colorectal cancer in Ashkenazi Jews, and has recently been associated with an increased risk for breast cancer in the same population. In that study, we genotyped 205 paraffin-embedded breast cancers from Ashkenazi Jewish women diagnosed below the age of 65. We now present an extended analysis, with clinicopathological correlations between carriers of I1307K and non-carriers. Twenty-four of 209 cases (11.5%, 95% confidence interval 7.5-16.6) were found to carry the I1307K polymorphism. When stratifying the data by other relevant clinicopathological variables, we observed no association between the presence of this polymorphism and age at diagnosis (P = 0.52), grade (P = 0.074), tumour size (P = 0.99), lymph node status (P = 0.82), oestrogen receptor status (P = 0.23) or P53 immunoreactivity (P = 0.80). The breast-cancer specific 5-year survival for women with I1307 K polymorphism was 88.9% compared with 81.6% in women without I1307K (P = 0.34). Using microdissected samples and direct sequencing, no somatic mutations were observed in any of the 24 I1307K-positive cases. Single-strand conformation analysis of 158 of the I1307K-negative breast cancers that were available for study revealed no mobility shifts. We conclude that the presence of the I1307K polymorphism does not appear to be associated with any particular clinicopathological feature of breast cancer and importantly, does not affect the prognosis.
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PMID:The effect of the I1307K APC polymorphism on the clinicopathological features and natural history of breast cancer. 1055 57

We prospectively studied the alterations of coagulation during adjuvant CNF (Cyclophosphamide, Novantrone--Mitoxantrone, 5-Fluorouracil) chemotherapy in patients with stage II breast cancer. In 50 consecutive stage II breast cancer patients (pre-peri-postmenopausal), and 50 controls, serial coagulation parameters including prothrombin time (P.T.), partial thromboplastin time (P.T.T.), fibrinogen, fibrinogen/fibrin degradation products (F.D.P.), protein C, protein S, antithrombin III (AT-III) and platelet count were performed. Blood samples for coagulation tests were collected at pretherapy, midtherapy (before the 3rd course), before the 6th course of chemotherapy, and 2 months after the cessation of therapy (post-therapy) of 6 cycles of adjuvant chemotherapy (Cyclophosphamide 500 mg/m2, Novantrone 10 mg/m2, 5-Fluorouracil 500 mg/m2). Chemotherapy was repeated every 3 weeks. None of our stage II breast cancer patients receiving adjuvant CNF chemotherapy developed thromboembolic complications. Before any treatment all the tested coagulation parameters were within the normal limits as compared to controls. No statistically significant changes of FDP were noted throughout the study. Fibrinogen, plasma protein C, protein S and AT-III were significantly decreased during chemotherapy. This decline was more evident at midtherapy. Their levels returned to the pretherapy values 2 months after the completion of chemotherapy. The P.T. was statistically shortened, while the P.T.T. showed a statistically significant prolongation during chemotherapy. In conclusion, it appears that monitoring stage II breast cancer with sophisticated coagulation tests during adjuvant CNF chemotherapy can not identify patients at high risk for thromboembolic events. These serially performed coagulation tests, could be considered as a cost-intensive monitoring and not justifiable as a screening for breast cancer patients receiving adjuvant chemotherapy. However, the increasing number of reports of life-threatening and sometimes fatal thromboembolic events following chemotherapy or hormonochemotherapy are of great concern. Our results suggest caution when using chemotherapeutic agents in patients with other thrombosis risk factors, since a significant decrease of protein C and protein S was observed in all patients. Additional studies are required to determine the exact association between chemotherapy and/or hormonochemotherapy and thrombotic events.
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PMID:Effects on blood coagulation of adjuvant CNF (cyclophosphamide, novantrone, 5-fluorouracil) chemotherapy in stage II breast cancer patients. 1062 46

DC are professional APC that are promising adjuvants for clinical immunotherapy. Methods to generate in vitro large numbers of functional human DC using either peripheral blood monocytes or CD34+ pluripotent HPC have been developed recently. However, the various steps of their in vitro production for further clinical use need to fit good manufacturing practice (GMP) conditions. Our study focused on setting up such a full procedure, including collection of mononuclear cells (MNC) by apheresis, separation of monocytes by elutriation, and culture of monocytes with GM-CSF + IL-13 + autologous serum (SAuto) in sterile Teflon bags. The procedure was first developed with apheresis products from 7 healthy donors. Its clinical feasibility was then tested on 7 patients with breast cancer. The characteristics of monocyte-derived DC grown with SAuto (or in some instances with a pooled AB serum) were compared with those obtained in the presence of FBS by evaluation of their phenotype, their morphology in confocal microscopy, and their capacity to phagocytize latex particles and to stimulate allogeneic (MLR) or autologous lymphocytes (antigen-presentation tests). The results obtained demonstrate that the experimental conditions we set up are easily applicable in clinical trials and lead to large numbers of well-defined SAuto-derived DC as efficient as those derived with FBS.
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PMID:In vitro generation of dendritic cells from human blood monocytes in experimental conditions compatible for in vivo cell therapy. 1081 24

Effects of "classical" and "modified" adjuvant CMF-chemotherapy on haemostasis were studied in 22 patients with breast cancer receiving cyclophosphamide (100 mg/m2 p.o.; days 1-14 or 600 mg/m2 i.v.; days 1,8), methotrexate (40 mg/m2 i.v.; days 1,8) and 5-fluorouracil (600 mg/m2 i.v.; days 1,8). Blood collection was done prior to chemotherapy on day 1 and 8. A significant decrease of protein C antigen and activity associated with cumulative effects was observed from day 1 to 8. This effect was similar with "classical" and "modified" CMF-chemotherapy but the reduction of protein C was more pronounced with the oral application of cyclophosphamide. In absence of any significant cumulative decrease of other vitamin K-dependent blood coagulation proteins (factor VII, protein S), the simultaneous decrease of protein C activity and antigen indicates a specific influence of CMF-chemotherapy on vitamin K-dependent protein C-synthesis in the liver.
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PMID:Adjuvant CMF-chemotherapy and haemostasis. Effect of "classical" and "modified" adjuvant CMF-chemotherapy on blood coagulation fibrinolysis in patients with breast cancer. 1084 73

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.
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PMID:Decreased E-cadherin augments beta-catenin nuclear localization: studies in breast cancer cell lines. 1117 84

Participation of E-cadherin in the Wnt signaling pathway was suggested because of the dual role of beta-catenin in cell adhesion and the Wnt signaling cascade. Whereas beta-catenin interacts at the cell membrane with the cell adhesion protein E-cadherin, in the nucleus it activates Wnt target genes through formation of transcriptionally active complexes with members of the Tcf/Lef family of transcription factors. Here, we analyzed by PCR and direct cycle sequencing 26 human breast cancer cell lines for alterations in the E-cadherin gene. Genetic alterations were identified in eight cell lines. Five cell lines had truncating mutations, whereas three cell lines had in-frame deletions in the gene transcript and expressed mutant E-cadherin proteins at the cell membrane. Involvement of E-cadherin in the Wnt pathway was evaluated through determination of the activity of a Tcf reporter gene, which had been transiently transfected into 15 breast cancer cell lines. None of six E-cadherin mutant cell lines and four cell lines that exhibit transcriptional silencing of the E-cadherin gene showed Tcf-mediated transcriptional activation. E-cadherin wild-type cell line DU4475 exhibited constitutive Tcf-beta-catenin signaling activity and was found to express truncated APC proteins. These results indicate that if cellular transformation occurred through mutation of E-cadherin, it is not mediated via constitutive activation of the Wnt signaling pathway.
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PMID:Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. 1119 75

Inherited BRCA2 mutations predispose individuals to breast cancer and increase risk at other sites. Recent studies have suggested a role for the APC I1307K allele as a low-penetrance breast cancer susceptibility gene that enhances the phenotypic effects of BRCA1 and BRCA2 mutations. To model the consequences of inheriting mutant alleles of the BRCA2 and APC tumor suppressor genes, we examined tumor outcome in C57BL/6 mice with mutations in the Brca2 and Apc genes. We hypothesized that if the Brca2 and Apc genes were interacting to influence mammary tumor susceptibility, then mammary tumor incidence and/or multiplicity would be altered in mice that had inherited mutations in both genes. Female and male offspring treated with a single IP injection of 50 mg/kg N-ethyl-N-nitrosourea (ENU) at 35 days of age developed mammary adenoacanthomas by 100 days of age. The female Apc-mutant and Brca2/Apc double-mutant progeny had mean mammary tumor multiplicities of 6.7+/-2.8 and 7.2+/-2.7, respectively, compared to wild-type and Brca2-mutant females, which had mean mammary tumor multiplicities of 0.1+/-0.4 and 0.3+/-0.5, respectively. Female ENU-treated Apc-mutant and Brca2/Apc double heterozygotes were also susceptible to premature ovarian failure. Thus, the inheritance of an Apc mutation predisposes ENU-treated female and male mice to mammary tumors and, in the case of female mice, to ovarian failure. These results indicate that mammary tumor development in Apc-mutant mice can progress independently of ovarian hormones. The Apc mutation-driven phenotypes were not modified by mutation of Brca2, perhaps because Brca2 acts in a hormonally dependent pathway of mammary carcinogenesis.
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PMID:Mammary tumor induction and premature ovarian failure in ApcMin mice are not enhanced by Brca2 deficiency. 1121 75

Induction of procoagulant factors in malignant cells is considered to be the major cause of coagulation disorders in cancer. Thrombomodulin (TM), a negative regulator of coagulation was also found to be expressed in cancer cells. We report here evidence for another anticoagulant, the endothelial cell protein C receptor (EPCR), in cancer cells. EPCR was detected in several cell lines derived from various types of cancer. Significant levels of protein C (PC) activation were detected only with cell lines expressed both EPCR and TM. Anti-EPCR monoclonal antibodies (mAbs) specifically inhibited the activation. Thus, EPCR function appears to be important for PC activation by cancer cells. In addition, we detected EPCR expression in tumor cells from breast cancer patients, with an extremely high frequency. EPCR function may contribute to progression or pathogenesis of some types of cancer, and may explain the complexity of coagulopathy in cancer patients.
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PMID:Expression and anticoagulant function of the endothelial cell protein C receptor (EPCR) in cancer cell lines. 1124 60


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