UMLS:C0006142 - FACTA Search

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

Since experimental studies have shown that tumour necrosis factor-alpha (TNF-alpha) has potent anti-tumour activity that can be potentiated with cytokines, we tested the efficacy of TNF-alpha with interferon-gamma (IFN-gamma) on different human breast cancer cell lines, particularly comparing hormone-dependent and -independent phenotypes. TNF-alpha inhibited the growth of hormone-dependent human MCF-7, ZR-75-1 and T47-D breast cancer cells with a half maximal concentration of 0.25 nM. In contrast, the growth of hormone-independent cells MDA-MB-231 and HS578T was not affected by TNF-alpha alone, but a synergistic inhibition was observed when using IFN-gamma and TNF-alpha together. The mRNA for the proto-oncogene C-MYC, as an intracellular indicator of cell activation, was significantly increased in MCF-7 cells in the presence of TNF-alpha. In MDA-MB-231 cells this mRNA was increased only in the presence of both TNF-alpha and IFN-gamma, without a change in the number of surface TNF receptors. These findings indicate that TNF-alpha treatment in combination with IFN-gamma may provide a successful approach to overcome the cellular heterogeneity of advanced breast tumours.
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PMID:Tumour necrosis factor and interferon are selectively cytostatic in vitro for hormone-dependent and hormone-independent human breast cancer cells. 903 15

Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer. Retinoic acid receptor-gamma (RAR-gamma) has been shown to mediate the antiproliferative activity of retinoids. To further test this hypothesis we examined the effects of different RAR-gamma selectively binding retinoids (CD2325, CD2247, CD666 and CD437) on breast cancer cell lines. With exception of CD2247, all retinoids inhibited proliferation of MCF-7, SKBR-3, T47D and ZR-75-1 breast cancer cell lines, similar to the natural compound all-trans retinoic acid (ATRA). In addition, all 4 compounds were able to act synergistically with interferon-gamma (IFN-gamma) in all breast cancer cell lines including the retinoid-resistant BT-20 and 734-B lines. In functional transactivation assays we demonstrated that only in the MCF-7 cell line, TPA-mediated AP-1 activity was suppressed only by ATRA and CD2325, whereas in SKBR-3, another RA-sensitive breast cancer cell line, it was not. The synergistic antiproliferative activity involving retinoids and IFN-gamma could not be explained by an enhanced anti-AP-1 activity. No correlation was found between expression of RARs and cellular retinoic acid binding proteins (CRABPs) and antiproliferative effects of the retinoids. RAR-gamma selectively binding retinoids are potent inhibitors of breast cancer cell proliferation, alone and in combination with IFN-gamma. For this reason and because of a possible low toxicity, as compared with retinoic acid, we speculate that these RAR-gamma selective binding retinoids might be of clinical importance.
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PMID:Activity of retinoic acid receptor-gamma selectively binding retinoids alone and in combination with interferon-gamma in breast cancer cell lines. 913 90

Tamoxifen (TAM) is used in the prevention and treatment of breast cancer, however, its mechanisms of therapeutic action as well as its pathologic effects are not fully understood. We report that TAM (10(-7)-10(-5) M) inhibits 3-methylcholanthrene-induced transformation of C3H 10T1/2 murine fibroblasts in a dose-responsive manner. Over this concentration range, TAM (>10(-6) M) potentiates inducible nitric oxide synthase (iNOS) activity in 10T1/2 cells. This increase in NO synthase activity was mediated through an increase in iNOS protein for cells stimulated with interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS). Significant increases in NO formation were observed when TAM (10(-5)) was added prior to or simultaneously with IFN-gamma/LPS treatment, whereas the addition of TAM 48 h after IFN-gamma/LPS treatment had no effect on NO synthesis. The morphologic changes seen with cells treated with TAM are similar to those observed in cells treated with TGF-beta1. TGF-beta1 inhibited NO production at high doses and slightly enhanced NO formation at low doses in IFN-gamma/LPS-stimulated cells. The transformation inhibitory effects of TAM did not appear to be related to the effects on cellular proliferation of neoplastic cells as TAM did not inhibit the growth of neoplastic cells into foci in the presence of normal confluent C3H 10T1/2 fibroblasts.
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PMID:Effects of tamoxifen on nitric oxide synthesis and neoplastic transformation in C3H 10T1/2 fibroblasts. 946 93

CD40 is present on B cells, monocytes, dendritic cells, and endothelial cells, as well as a variety of neoplastic cell types, including carcinomas. CD40 stimulation by an antibody has previously been demonstrated to induce activation-induced cell death in aggressive histology human B-cell lymphoma cell lines. Therefore, we wanted to assess the effects of a recombinant soluble human CD40 ligand (srhCD40L) on human breast carcinoma cell lines. Human breast carcinoma cell lines were examined for CD40 expression by flow cytometry. CD40 expression could be detected on several human breast cancer cell lines and this could be augmented with interferon-gamma. The cell lines were then incubated with a srhCD40L to assess effects on in vitro growth. srhCD40L significantly inhibited the proliferation of the CD40(+) human breast cancer cell lines. This inhibition could also be augmented with interferon-gamma. Viability was also affected and this was shown to be due to increased apoptosis of the cell lines in response to the ligand. Treatment of tumor-bearing mice was then performed to assess the in vivo efficacy of the ligand. Treatment of tumor-bearing SCID mice with the ligand resulted in significant increases in survival. Thus, CD40 stimulation by its ligand directly inhibits human breast carcinoma cells in vitro and in vivo. These results suggest that srhCD40L may be of clinical use to inhibit human breast carcinoma growth.
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PMID:Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand. 1021 96

Interleukin-2 (IL-2), a product of activated T-cells, is now being used in a number of protocols for cancer immunotherapy. In one stem cell transplantation protocol for breast cancer, IL-2 is used together with interferon-gamma (IFN-gamma) and cyclosporine to stimulate a graft-versus-tumor response and improve the likelihood of a prolonged remission. We present the case of a patient who developed peripheral eosinophilia, perihilar infiltrates, and hypoxemia after autologous stem cell transplantation and the use of recombinant IL-2 and IFN-gamma. Histologic analysis of transbronchial lung biopsies demonstrated a few eosinophils within the bronchial submucosa. Immunostaining using antibodies directed against eosinophil major basic protein (MBP), however, revealed massive extracellular deposition of this toxic granule protein throughout the lung parenchyma. IL-2 therapy is well known to induce a peripheral eosinophilia and to be associated with the capillary leak syndrome characterized by weight gain, edema, and oliguria. The findings noted in this case report suggest that the eosinophil activation that accompanies immunologic therapy with IL-2 can result in direct toxicity to the lung and a localized vascular leak syndrome. This syndrome should be considered in the differential diagnosis of pulmonary infiltrates that occur acutely after bone marrow transplantation with cytokine augmentation.
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PMID:Pulmonary infiltrates after cytokine therapy for stem cell transplantation. Massive deposition of eosinophil major basic protein detected by immunohistochemistry. 1050 29

Using a murine breast cancer model, we earlier found a positive correlation between the expression of nitric oxide synthase (NOS) and tumor progression; treatment with inhibitors of NOS, N(G)-methyl-L-arginine (NMMA) and N(G)-nitro-L-arginine methyl ester (L-NAME), had antitumor and antimetastatic effects that were partly attributed to reduced tumor cell invasiveness. In the present study, we used a novel in vivo model of tumor angiogenesis using subcutaneous implants of tumor cells suspended in growth factor-reduced Matrigel to examine the angiogenic role of NO in a highly metastatic murine mammary adenocarcinoma cell line. This cell line, C3L5, expresses endothelial (e) NOS in vitro and in vivo, and inducible (i) NOS in vitro on stimulation with lipopolysaccharide and interferon-gamma. Female C3H/HeJ mice received subcutaneous implants of growth factor-reduced Matrigel inclusive of C3L5 cells on one side, and on the contralateral side, Matrigel alone; L-NAME and D-NAME (inactive enantiomer) were subsequently administered for 14 days using osmotic minipumps. Immediately after sacrifice, implants were removed and processed for immunolocalization of eNOS and iNOS proteins, and measurement of angiogenesis. Neovascularization was quantified in sections stained with Masson's trichrome or immunostained for the endothelial cell specific CD31 antigen. While most tumor cells and endothelial cells expressed immunoreactive eNOS protein, iNOS was localized in endothelial cells and some macrophages within the tumor-inclusive implants. Measurable angiogenesis occurred only in implants containing tumor cells. Irrespective of the method of quantification used, tumor-induced neovascularization was significantly reduced in L-NAME-treated mice relative to those treated with D-NAME. The quantity of stromal tissue was lower, but the quantity of necrotic tissue higher in L-NAME relative to D-NAME-treated animals. The total mass of viable tissue (ie, stroma and tumor cells) was lower in L-NAME relative to D-NAME-treated animals. These data suggest that NO is a key mediator of C3L5 tumor-induced angiogenesis, and that the antitumor effects of L-NAME are partly mediated by reduced tumor angiogenesis.
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PMID:Nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. 1051 20

Interaction of CD95 (Apo-1/Fas) and its ligand (CD95L) plays an important role in the regulation of the immune response, since CD95+ lymphocytes may be killed after engagement of the CD95 receptor. Studying the CD95/CD95L system in 40 cases of breast cancer, the malignant cells expressed CD95L, but lost CD95 expression, when compared with non-malignant mammary tissue. Jurkat T cells incubated on breast cancer sections underwent CD95L-specific apoptosis. The rate of apoptosis correlated with the CD95L mRNA levels of the tissue samples. In four breast cancer cell lines, CD95L expression was increased by interferon-gamma (IFN-gamma), which resulted in higher levels of CD95L-specific apoptosis in co-cultured Jurkat T cells. Since IFN-gamma is mainly secreted by activated T cells, up-regulation of CD95L in breast cancer cells in response to IFN-gamma may thus counterselect activated tumour-infiltrating T cells and favour the immune escape of breast cancer. As demonstrated by inhibition of matrix metalloproteinases, CD95L expressed on breast cancer cells can also be shed from the cell membrane into the culture supernatant. Supernatants derived from cultured breast cancer cells induced apoptosis in Jurkat T cells via CD95L. In breast cancer patients, depletion of CD4+ and CD8+ peripheral blood lymphocytes was significantly correlated with CD95L expression in the tumours. This might be suggestive for a relationship between CD95L expression by breast cancer and systemic immunosuppression.
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PMID:CD95 ligand expression as a mechanism of immune escape in breast cancer. 1065 43

Dendritic cells (DCs) are powerful antigen-presenting cells. Because DCs are rare cells, methods to produce them in vitro are valuable ways to study their biologic properties and to generate cells for immunotherapy. This study defines the antigen-presenting properties of DCs generated in vitro from CD34+ cells of patients with breast cancer. The combination of cytokines flt3 ligand + c-kit ligand + granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin-4 (IL-4) + tumor necrosis factor-alpha (TNF-alpha) was used to maximize the output of mature DCs in the culture of CD34+ cells while minimizing the production of monocytes. Cells grew and differentiated into DCs as measured by a time-dependent upregulation of cell surface antigens major histocompatibility complex class II, CD1a, CD80, CD86, CD40, and CD4, so that 40% +/- 9% (n = 6) of cells in culture at day 15 were CD1a+CD14-. Markers were acquired in the same sequence as on monocytes induced to differentiate with GM-CSF + IL-4. Differentiation was marked by a time-dependent increase in allostimulatory function, which, at its peak, was more potent than in cultures of DCs generated from monocytes with GM-CSF + IL-4, but was comparable on a cell-to-cell basis to that of mature monocytes cultured in flt3-ligand + c-kit-ligand + GM-CSF + IL-4 + TNF-alpha. Both CD34+ cell-derived and monocyte-derived DCs were able to process and to present tetanus toxoid and keyhole limpet hemocyanin to autologous T cells and to present major histocompatibility class I-binding peptides to CD8+ cytotoxic T lymphocytes inducing interferon-gamma production. Altogether, these results suggest that DCs generated from CD34+ cells of patients with breast cancer with flt3 ligand, c-kit ligand, GM-CSF, IL-4, and TNF-alpha are competent antigen-presenting cells, particularly for CD8+ cytotoxic T lymphocytes, and resemble mature monocyte-derived DCs in the assays described here.
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PMID:Dendritic cells generated from CD34+ progenitor cells with flt3 ligand, c-kit ligand, GM-CSF, IL-4, and TNF-alpha are functional antigen-presenting cells resembling mature monocyte-derived dendritic cells. 1068 37

Several laboratories have reported anti-tumor activity for high levels of interleukin-10 (IL-10) expressed as a transgene or administered as recombinant protein. The authors have reported a positive correlation for nitric oxide production and anti-tumor activity of IL-10 in a murine model of breast cancer. In the current study, they sought evidence of a mechanistic role for nitric oxide in IL-10-mediated tumor growth inhibition. They wanted to determine whether pharmacologic inhibition of nitric oxide synthase (NOS) activity reverses the therapeutic effect of IL-10. Administration of either of two NOS inhibitors, aminoguanidine (AG) or L-lysine,N6-1-iminoethyl-dihydrochloride, appears to abrogate in part the tumor growth inhibition observed when IL-10 is overexpressed as a transgene in two murine mammary tumor cell lines. Nitric oxide levels were assessed at the tumor site by measuring nitrosylated heme levels by electron spin resonance spectroscopy. Nitric oxide hemoglobin levels were lower in tumors from aminoguanidine-treated mice, indicating that effective inhibition of nitric oxide production occurred at the tumor site. Previous investigations showed that the inducible form of NOS protein (iNOS), but not constitutive NOS, was expressed at higher levels in IL-10-expressing tumors. Because iNOS is regulated at the transcriptional level, the authors compared iNOS mRNA levels in IL-10 and control tumors. Northern analysis revealed strong iNOS message expression in all six IL-10-expressing tumors examined, whereas message was faintly detected in parental or 66-neo tumors. The inducible form of NOS is responsive to induction by interferon-gamma (IFN-gamma). The role of IFN-gamma in IL-10-mediated tumor inhibition and iNOS mRNA induction was determined. When tumors were transplanted to IFN-gamma mutant mice, the tumor-inhibitory activity of IL-10 was lost. Furthermore, iNOS mRNA was no longer induced in the absence of host expression of IFN-gamma. These data indicate that nitric oxide contributes to the anti-tumor activity of IL-10 and that expression of iNOS in this context depends on IFN-gamma.
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PMID:Essential role of nitric oxide and interferon-gamma for tumor immunotherapy with interleukin-10. 1074 47

This study was designed to determine whether in vitro exposure of isolated short-term human primary and metastatic breast tumor cell cultures to interferon-gamma (IFN-gamma) could enhance expression of the breast tumor associated DF3 antigen in association with the intercellular adhesion molecule 1 (ICAM-1) and MHC class II molecules. Cell cultures were established from primary solid tumors and metastatic cells as previously described (Sgagias et al., 1995). Data show that recombinant human IFN-gamma treatment, in vitro, dramatically increased the breast tumor associated DF3 antigen, in association with ICAM-1, and MHC class II antigens in primary breast cancer cell cultures. All primary breast tumor cell cultures constitutively expressed high levels of HLA-class I antigen. Metastatic breast cancer cell cultures expressed high levels of DF3 and recombinant human IFN-gamma treatment, in vitro, upregulated ICAM-1 and MHC class II antigens before and after passage of the metastatic cells through the nude mouse. Metastatic breast cancer cells similar to primary breast cancer cells constitutively expressed high levels of MHC class I antigens. In addition, three LAK cell lines significantly lysed the primary and the metastatic breast tumor cell cultures to the same degree before and after passage of the metastatic cancer cells through the nude mouse. These data indicate the upregulation of the breast tumor associated DF3 antigen in vitro after IFN-gamma treatment and its persistence in vivo, after passage of the metastatic breast cancer cells through the nude mouse. The ability of IFN-gamma to upregulate the breast tumor associated DF3 antigen in association with the ICAM-1 and HLA class II antigens may play an important role in eliciting an immune response which may contribute to the immunodiagnosis, and immunotherapy of breast cancer.
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PMID:Upregulation of DF3, in association with ICAM-1 and MHC class II by IFN-gamma in short-term human mammary carcinoma cell cultures. 1085 35

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