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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years cellular homologues of many viral oncogenes have been identified. As these genes are partially homologous to viral oncogenes and are activated in some tumour cell lines they are termed "proto-oncogenes". In tumour cell lines proto-oncogenes are activated by either quantitative or qualitative changes in gene structure: activation of these genes was originally thought to be a necessary primary event in carcinogenesis, but activated cellular oncogenes, unlike viral oncogenes, do not transform normal cells in culture. In experimental models cooperation between two oncogenes can induce transformation of early passage cells, and this has become the basis of an hypothesis for multistep carcinogenesis. Proto-oncogene products also show sequence homology to various components in the mitogenic pathway (growth factors, growth factor receptors, signal transducing proteins and nuclear proteins), and it has been postulated that they may cause deregulation of the various components of this pathway. In human tumours single or multiple oncogene activation occurs. The pattern of oncogene activation in common solid malignancies is not consistent within any one class of tumour, nor is it uniform between classes, with three exceptions. In neuroblastoma, breast cancer, and perhaps in lung cancer there is relatively consistent activation of N-myc, neu, and c-myc/N-myc, respectively. Amplification of these genes generally correlates with poor prognosis. The introduction of methods for the direct study of oncogene transcription and their products will undoubtedly broaden our vision of cancer biology in man and, hopefully, add diagnostic and prognostic precision to tumour typing.
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PMID:Cellular oncogenes in neoplasia. 331 99

We have examined the genomic organisation of c-myc, N-myc, L-myc, neu and N-ras in tissue from 41 breast carcinomas, lymph node metastases from 10 of these carcinomas, one fibrosarcoma, 10 cases of benign fibrocystic breast and six fibroadenomas. We have not observed an alteration in either N-myc or N-ras in any of the samples studied. We have seen a 2-fold amplification of L=myc in DNA from one infiltrating ductal (ID) carcinoma, but otherwise we have seen no alterations to this gene. Amplification of c-myc was seen in 22% of ID breast carcinoma sample. Levels of amplification ranged from 2- to 10-fold. We have found a significant (p less than 0.02) correlation between an altered c-myc gene and a very poor short-term prognosis. Amplification of neu was seen in 19% of ID breast carcinomas, but the levels of amplification were higher than those seen for c-myc. Alterations to neu also correlated well with poor short-term prognosis (p less than 0.0002). Finally, we have observed a low level of amplification of c-myc in DNA from a benign fibrocystic breast lesion. This lesion exhibited some features characteristic of those thought to be associated with an increased risk of developing breast cancer.
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PMID:Alterations to either c-erbB-2(neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. 333 Jul 85

Inappropriate expression of Her-2/neu (ERBB2) gene has been associated with impaired breast cancer prognosis, suggesting a functional role in tumor progression. Herein we describe a quantitative method for analysis of Her-2/neu gene messenger RNA (mRNA), which employs reverse transcriptase polymerase chain reaction (RT-PCR) on a 10-microns cryostat section. The technique combines modified RNA extraction with complementary DNA (cDNA) synthesis to achieve a high level of sensitivity. Utilizing this PCR-based gene expression assay, we were able to quantitate variable amounts of Her-2/neu mRNA in cell lines with established levels of gene expression and in clinical human breast cancer specimens. In clinical samples, mRNA levels correlated with intensity of immunoperoxidase staining for corresponding oncoprotein. We conclude that PCR-based mRNA quantitation can be applied to quantitative analysis of Her-2/neu gene expression, and potentially many other genes, in samples of limited size.
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PMID:Quantitative analysis of Her-2/neu (ERBB2) gene expression using reverse transcriptase polymerase chain reaction. 750 83

The development of T-cell therapy for the treatment of human malignancy has been hindered, in large part, by a lack of identifiable tumor antigens. Studies to identify potential T-cell targets in humans have been difficult because of practical problems limiting the use of in vivo immunization and a lack of reproducible in vitro priming methods. Oncogenic proteins are involved in malignant transformation and maintenance of the transformed phenotype and theoretically are potential targets to T-cell therapy. HER-2/neu protein is a protooncogene product overexpressed in a variety of human malignancies and is associated with malignant transformation and aggressive disease in human breast cancer. Previous studies have shown that some patients with breast cancer have existent helper/inducer T-cell immunity to p185HER-2/neu protein and peptides. The current study represents initial attempts to identify candidate cytotoxic T-lymphocyte (CTL) epitopes. Synthetic peptides were constructed identical to HER-2/neu protein segments with amino acid motifs similar to the published motif for HLA-2.1-binding peptides. Four peptides were synthesized and two were shown to be avid binders to HLA-A2.1. Two of the four peptides could be shown to elicit peptide-specific CTL by primary in vitro immunization in a culture system using peripheral blood lymphocytes from a normal individual homozygous for HLA-A2. p185HER-2/neu protooncogene protein contains immunogenic epitopes capable of generating human CD8+ CTL. The identification of candidate CTL epitopes will allow studies to determine whether some cancer patients have existent CTL immunity to HER-2/neu protein. The demonstrated ability to generate human peptide-specific CTL in vitro allows screening of other oncogenic proteins to identify candidate T-cell epitopes potentially useful for future immunotherapy studies.
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PMID:In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein. 750 19

In Paget's disease of the breast, the epidermis contains large clear neoplastic cells. To explain the pathogenesis of this disease, the immunohistochemical characteristics of these cells were investigated in 25 patients. The cytoplasmic presence of low molecular weight cytokeratin and the absence of high molecular weight cytokeratin in all cases confirmed the glandular origin of the Paget cells. Membrane over-expression of the neu-protein was established in 96% of cases. It was hypothesized that epidermal keratinocytes release a chemotactic factor which attracts neu-over-expressing breast carcinoma cells by chemotaxis into the epidermis. The biological assays showed that normal keratinocytes release one or more chemotactic factor(s) into their conditioned medium, which induced spreading and motility of neu-over-expressing SK-BR-3 human breast cancer cells. The conditioned medium of keratinocytes also attracted the SK-BR-3 cells by chemotaxis in a modified Boyden chamber. Furthermore, MCF-7 human breast cancer cells, which do not over-express the neu-protein, were not attracted by chemotaxis of conditioned medium of human keratinocytes. The involvement of the neu-protein in spreading, motility and chemotaxis is further indicated by the inhibition of these processes by monoclonal antibodies against the extracellular domain of the neu-protein. We conclude, therefore, that the Paget cells spread through the epidermis due to the motility induced by a chemotactic factor, which is released by epidermal keratinocytes and whose influence is mediated by the neu-protein.
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PMID:Keratinocyte induced chemotaxis in the pathogenesis of Paget's disease of the breast. 751 65

Antagonists of steroid hormones are clinically important in the management of breast cancer. However, the duration of response is limited due to the development of hormone-independent tumors in virtually all cases. In an attempt to obtain insight into the mechanisms underlying antiestrogen resistance, the consequences of epigenetic changes in gene expression were studied in vitro. Estrogen-dependent ZR-75-1 human breast cancer cells were treated with 5-azacytidine, an inhibitor of DNA methylation, and cultured in the absence of estradiol or in the presence of antiestrogens. Estrogen-independent cell colonies developed within 3 weeks at high frequency in 5-azacytidine-treated cultures (0.7 x 10(-3), in contrast to control cultures (< or = 10(-8). The derived cells (ZR/AZA) were resistant to 4-hydroxytamoxifen and ICI 164,384, independent of the selection protocol, but had lost the ability to grow anchorage-independent. Whereas expression of estrogen receptor, progesterone receptor, and pS2 were down-regulated, expression of epidermal growth factor (EGF) receptor and HER2/neu were increased in ZR/AZA cells. In contrast to the stable altered expression patterns of estrogen receptor and EGF receptor, transient keratin 7 expression was observed. Transforming growth factor-alpha mRNA was identified in ZR-75-1 cells and ZR/AZA cells and EGF-like peptides were secreted in the culture medium. Proliferation of ZR/AZA cells could be partially inhibited with an EGF receptor-blocking antibody. Presence of both growth factor receptors and possible ligands suggests the development of an autocrine growth mechanism. Our data show that epigenetic alterations of gene expression result in rapid progression of breast cancer cells to hormone independence.
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PMID:Induction of estrogen independence of ZR-75-1 human breast cancer cells by epigenetic alterations. 753 60

With his colleagues at McMaster University in Hamilton, Ont., molecular biologist Dr. William J. Muller has developed strains of transgenic mice to study the roles of certain genes in the development of mammary epithelial cancer. Genes of particular interest include neu, which codes for a growth factor receptor, and c-src, one of the first oncogenes ever described. The outcome of this work is a better understanding of how breast cancer starts and of the prognosis for patients with certain forms of the disease. It is expected that murine models will also be used to test the efficacy of new therapies for breast cancer.
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PMID:Mouse models and breast cancer. 755 21

2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificity for the c-erbB-2 and Fc gamma RIII extracellular domains. This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-erbB-2 gene product of the HER2/neu proto-oncogene by human natural killer cells and mononuclear phagocytes expressing the Fc gamma RIII A isoform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-overexpressing tumors were treated with 1 h i.v. infusions of 2B1 on days 1, 4, 5, 6, 7, and 8 of a single course of treatment. Three patients were treated with daily doses of 1.0 mg/m2, while six patients each were treated with 2.5 mg/m2 and 5.0 mg/m2, respectively. The principal non-dose-limiting transient toxicities were fevers, rigors, nausea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at the 5.0 mg/m2 dose level in two patients who had received extensive prior myelosuppressive chemotherapy. Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding properties were retained. The pharmacokinetics of this murine antibody were variable and best described by nonlinear kinetics with an average t 1/2 of 20 h. Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma. Brisk human anti-mouse antibody responses were induced in 14 of 15 patients. Several minor clinical responses were observed, with reductions in the thickness of chest wall disease in one patient with disseminated breast cancer. Resolution of pleural effusions and ascites, respectively, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon cancer. Treatment with 2B1 BsMAb has potent immunological consequences. The maximum tolerated dose and Phase II daily dose for patients with extensive prior myelosuppressive chemotherapy was 2.5 mg/m2. Continued dose escalation is required to identify the maximally tolerated dose for patients who have been less heavily pretreated.
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PMID:Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 755 34

The incidence of amplification of neu oncogene-encoded protein tyrosine kinase in human breast cancer strongly supports the concept that protein tyrosine phosphorylation and dephosphorylation are key regulatory mechanisms in the proliferation, differentiation, and neoplastic transformation of breast epithelial cells. We examined the potential regulatory role of protein tyrosine phosphatases (PTPases) in the maintenance of cellular tyrosine phosphorylation by the introduction of leukocyte common-antigen-related PTPase (LAR-PTPase) cDNA into a tumorigenic human breast carcinoma cell line that overexpressed p185neu protein tyrosine kinase. The transfected human breast carcinoma cells expressed elevated levels of LAR-PTPase as assessed by reverse transcription-polymerase chain reaction and by analysis of LAR-PTPase protein. The LAR-PTPase-transfected human breast carcinoma cells had a significantly (P < 0.01) slower proliferation rate in vitro than control-transfected cells. When LAR-PTPase-transfected cells were inoculated into athymic nude mice, a consistent and significant (P < 0.05) suppression of tumor growth was observed. These results provide evidence that a specific PTPase, LAR-PTPase, can play a suppressive regulatory role in the tumor growth of human breast carcinoma cells that overexpress p185neu protein tyrosine kinase.
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PMID:LAR-PTPase cDNA transfection suppression of tumor growth of neu oncogene-transformed human breast carcinoma cells. 757 97

Females from a mouse lineage transgenic for the activated rat neu oncogene under the control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) all develop breast tumors with high reproducibility within the first 2-3 months of life. These animals were crossed with mice from a lineage transgenic for the herpes simplex virus thymidine kinase gene (HSVtk) under the control of its own promoter and polyoma enhancer. Double transgenic mice (for both neu and tk) developed breast neoplasias with the same kinetics as the neu-only mice. Tumor-bearing double transgenic mice, treated intratumorally with the antiviral agent ganciclovir (GCV), showed an inhibiting effect on tumor growth. However, this effect was not seen either on GCV-treated neu-only transgenic mice or on saline-injected controls. This suggests that tk-engineered breast tumors are susceptible to GCV administered locally, and implies that neu-mice could be a useful model for testing the effectiveness of HSVtk-bearing vectors followed by systemic GCV on breast cancer cells.
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PMID:Local regression of breast tumors following intramammary ganciclovir administration in double transgenic mice expressing neu oncogene and herpes simplex virus thymidine kinase. 758 28


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