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

The Her-2/neu oncogene encodes a Mr 185,000 transmembrane protein with homology to the epidermal growth factor receptor. It is overexpressed in 30-40% of breast and ovarian cancers, and this overexpression was shown to correlate with aggressiveness of malignancy and poor prognosis. Using tumor-associated lymphocytes isolated from patients with ovarian or breast cancer, several HLA-A2-restricted, Her-2/neu-derived peptides were identified. Further studies revealed that these tumor-associated CTLs can also lyse other tumors, including non-small cell lung and pancreatic cancer cells, suggesting that Her-2/neu epitopes are shared between several distinct types of epithelial tumors. To analyze whether Her-2/neu epitopes are tumor-associated antigens for renal cell carcinoma (RCC) and colon carcinoma, we induced Her-2/neu peptide-specific CTL responses by primary in vitro immunization and used these CTLs to determine the presentation of Her-2/neu epitopes on human tumor lines. Autologous dendritic cells (DCs) generated from peripheral blood monocytes were pulsed with Her-2/neu-derived peptides E75 and GP2 and used as antigen-presenting cells for CTL priming. High CTL activity toward peptide-pulsed targets was obtained after two weekly restimulations. CTLs induced with DCs generated in the presence of TNF-alpha elicited a higher cytotoxic activity when they were stimulated with the cognate peptide than did CTLs induced with DCs grown in granulocyte macrophage colony-stimulating factor and interleukin 4 alone. The cytotoxicity of induced CTLs was antigen specific and HLA-A2 restricted. Furthermore, these CTLs lysed, in a MHC- and antigen-restricted fashion, not only breast cancer cells but also colon carcinoma and RCC cell lines expressing Her-2/neu. The cytotoxic activity against tumor cells was blocked by cold HLA-A2-positive targets pulsed with the cognate peptide in cold target inhibition assay and by anti-HLA-A2 monoclonal Ab. These results suggest that epitopes derived from Her-2/neu protein might be attractive candidates for broadly applicable vaccines and may prove useful for adoptive immunotherapies designed for colon carcinoma or RCC.
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PMID:Her-2/neu-derived peptides are tumor-associated antigens expressed by human renal cell and colon carcinoma lines and are recognized by in vitro induced specific cytotoxic T lymphocytes. 948 28

There is evidence from recent data that mistletoe extracts exert immunostimulatory properties which could explain their therapeutic effects observed in some tumor patients. Aim of our study was, therefore, to investigate the effect of a subcutaneous 16-weeks therapy with a mistletoe extract (ABNOBAviscum Mali, AM) on the cellular and humoral immune responses in eight breast cancer patients. Mistletoe therapy induced a strong initial proliferation of peripheral blood mononuclear cells (PBMC) in all individuals, which, however, decreased in six patients during the observation period, indicating that not only activating but also inhibitory mechanisms have been induced. In all supernatants of AM-stimulated cell cultures TNF-alpha or IL-6 were found, indicating the activation of cells of the monocyte-/macrophage lineage by mistletoe extracts. Further analyses revealed, that AM induced in vitro also the release of low amounts of IFN-gamma and IL-4 with individual variations. At the end of the therapy, a shift to Th1- related cytokines could be observed in the in vitro cell culture system. All patients produced anti-mistletoe lectin 1 antibodies of the IgG-type during therapy and in four of them additionally antibodies of the IgE-type were found. It, therefore, seems that AM can influence the Th1/Th2 balance and, in case of a Th1 shift, this may favourably influence the tumor growth.
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PMID:Modulation of the cellular and humoral immune responses of tumor patients by mistletoe therapy. 953 28

P43, a breast cancer-associated antigen, has been repeatedly described as an immunosuppressive factor. The objective of the present study was to investigate whether immune dysregulation induced by p43 affects the profile of cytokines secreted by mitogen-stimulated lymphocytes in breast cancer patients as compared with stimulated lymphocytes in women with benign tumors. The study consisted of 32 women undergoing surgical excision for a suspicious lesion in their breast. Histology revealed malignant breast disease in 20 patients and benign lesions in 10 patients. Lymphocytes isolated from peripheral blood were activated by Conconavalin A (Con A) with and without the addition of p43 and the concentrations of cytokines (IL-2, TNF-alpha, IFN-gamma, IL-4, IL-10 and IL-6) secreted into the culture medium were determined. Lymphocytes of patients with malignant breast disease stimulated with Con A secreted a significantly higher concentration of IL-10 compared with lymphocytes of patients with benign tumors. No significant differences were found between the two groups regarding the levels of IL-2, TNF-alpha, IFN-gamma and IL-4. Cytokine concentrations were analyzed according to the type 1/type 2 cytokine profile (IL-2, TNF and IFN-gamma and IL-4, IL-6 and IL-10, respectively). This analysis revealed no significant differences in IL-2, TNF or IFN-gamma between benign and malignant tumors. However, in the type 2 cytokines, lymphocytes from cancer patients secreted significantly higher levels of IL-4 (27.3 +/- 7.2 U/ml) and IL-10 (44.1 +/- 22.3 U/ml) than did the lymphocytes from patients with benign disease (21.4 +/- 7.3 and 1.8 +/- 0.3 U/ml, respectively). The addition of p43 to the culture medium significantly enhanced the levels of IL-4 secreted by lymphocytes in both groups of patients (malignant disease, from 27.3 +/- 9.2 to 40.7 +/- 6.3 U/ml; benign disease, from 21.4 +/- 7.3 to 28.4 +/- 2.1 U/ml). P43 antigen significantly enhanced the low levels of IL-10 in the benign lymphocytes (from 1.8 +/- 0.4 to 8.4 +/- 1.5 U/ml) while the high levels of IL-10 secreted by the PBL in patients with malignant tumors were not significantly increased (44.1 +/- 22.3 versus 50.1 +/- 12.6 U/ml). The study showed a difference in the immune response of lymphocytes between malignant and benign tumors. When the current results were analyzed according to the type of response, i.e. in terms of whether at least two cytokines of either type 1 or type 2 were elevated, a significant type 2 response was observed in the PBL of patients with malignant breast cancer (IL-10 and IL-4). These results may explain why antitumor response is impaired in patients with breast cancer.
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PMID:Activated lymphocytes from breast cancer patients express the characteristics of type 2 helper cells--a possible role for breast cancer-associated p43. 961 68

Sex steroids play a predominant role in the development and differentiation of normal mammary gland as well as in the regulation of hormone-sensitive breast cancer growth. There is evidence suggesting that local intracrine formation of sex steroids from inactive precursors secreted by the adrenals namely, dehydroepiandrosterone (DHEA) and 4-androstenedione (4-dione) play an important role in the regulation of growth and function of peripheral target tissues, including the breast. Moreover, human breast carcinomas are often infiltrated by stromal/immune cells secreting a wide spectra of cytokines. These might in turn regulate the activity of both immune and neoplastic cells. The present study was designed to examine the action of cytokines on 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) activities in human breast cancer cells. The various types of human 17beta-HSD (five types) and 3beta-HSD (two types), because of their tissue- and cell-specific expression and substrate specificity, provide each cell with necessary mechanisms to control the level of intracellular active androgens and estrogens. We first investigated the effect of exposure to IL-4 and IL-6 on reductive and oxidative 17beta-HSD activities in both intact ZR-75-1 and T-47D human breast cancer cells. In ZR-75-1 cells, a 6 d exposure to IL-4 and IL-6 decreased E2-induced cell proliferation, the half maximal inhibitory effect being exerted at 88 and 26 pM, respectively. In parallel, incubation with IL-4 and IL-6 increased oxidative 17beta-HSD activity by 4.4- and 1.9-fold, respectively, this potent activity being observed at EC50 values of 22.8 and 11.3 pM, respectively. Simultaneously, reductive 17beta-HSD activity leading to E2 formation was decreased by 70 and 40% by IL-4 and IL-6, respectively. Moreover, IL-4 and IL-6 exerted the same regulatory effects on 17beta-HSD activities when testosterone and 4-dione were used as substrates, thus strongly suggesting the expression of the type 2 17beta-HSD ZR-75-1 cells. In contrast, in T-47D cells, IL-4 increased the formation of E2, whereas IL-6 exerts no effect on this parameter. However, we found that T-47D cells failed to convert testosterone efficiently into 4-DIONE, thus suggesting that there is little or no expression of type 2 17beta-HSD in this cell line. The present findings demonstrate that the potent regulatory effects of IL-4 and IL-6 on 17beta-HSD activities depend on the cell-specific gene expression of various types of 17beta-HSD enzymes. We have also studied the effect of cytokines on the regulation of the 3beta-HSD expression in both ZR-75-1 and T-47D human breast cancer cells. Under basal culture conditions, there is no 3beta-HSD activity detectable in these cells. However, exposure to IL-4 caused a rapid and potent induction of 3beta-HSD activity, whereas IL-6 failed to induce 3beta-HSD expression. Our data thus demonstrate that cytokines may play a crucial role in sex steroid biosynthesis from inactive adrenal precursors in human breast cancer cells.
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PMID:Regulation of sex steroid formation by interleukin-4 and interleukin-6 in breast cancer cells. 969 68

Previous studies have characterized the reactivity of CD8+ CTLs with ovarian and breast cancer. There is little information about the antigens and epitopes recognized by CD4+ T cells in these patients. In this study, we analyzed the ability of T cells from peripheral blood mononuclear cells of breast cancer patients to recognize HER-2/neu (HER-2) peptides. We found that 13 of 18 patients responded by proliferation to at least one of the HER-2 peptides tested. Of these peptides, one designated G89 (HER-2: 777-789) was recognized by T cells from 10 patients. Seven of nine responding patients were HLA-DR4+, suggesting that this peptide is recognized preferentially in association with HLA-DR4. Analysis of the specificity and restriction of the cytokine responses to G89 by G89-stimulated T cells revealed that these cells secreted significantly higher levels of IFN-gamma than interleukin 4 and interleukin 10, suggesting priming for a Th0-T helper 1 response. The same pattern of cytokine responses was observed to the intracellular domain of HER-2 protein, suggesting that G89-stimulated T cells recognized epitopes of the HER-2 protein in association with HLA-DR4. Because HLA-DR4 is present in 25% of humans, characterization of MHC class II-restricted epitopes inducing Th0-T helper 1 responses may provide a basis for the development of multivalent HER-2-based vaccines against breast and ovarian cancer.
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PMID:Proliferative and cytokine responses to class II HER-2/neu-associated peptides in breast cancer patients. 971 33

We evaluated T-cell responses to mitogens and to defined antigens in breast cancer patients. Significant defects in responses to tetanus toxoid and influenza virus were observed in patients with advanced-stage breast cancer. To define whether these defects were associated with a defect in antigen presentation [dendritic cells (DCs)] or effector function (T cells), these cells were studied separately. Purified DCs from 32 patients with breast cancer demonstrated a significantly decreased ability to stimulate control allogeneic T cells, but stimulation of patient T cells with either control allogeneic DCs or immobilized anti-CD3 antibody resulted in normal T-cell responses, even in patients with stage IV tumors. These data suggest that reduced DC function could be one of the major causes of the observed defect in cellular immunity in patients with advanced breast cancer. We then tested whether stem cells from these patients could give rise to functional DCs after in vitro growth with granulocyte/macrophage colony-stimulating factor and interleukin 4. Normal levels of control allogeneic and tetanus toxoid-dependent T-cell proliferation were observed when DCs obtained from precursors were used as stimulators. Those cells also induced substantially higher levels of influenza virus-specific CTL responses than mature DCs from the peripheral blood of these patients, although responses did not quite reach control values. Thus, defective T-cell function in patients with advanced breast cancer can be overcome by stimulation with DCs generated from precursors, suggesting that these cells may better serve as autologous antigen carriers for cancer immunotherapy than mature peripheral blood DCs.
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PMID:Decreased antigen presentation by dendritic cells in patients with breast cancer. 981 9

Sex steroids play a crucial role in the development and differentiation of normal mammary gland as well as in the regulation of breast cancer growth. Local intracrine formation of sex steroids from inactive precursors secreted by the adrenals, namely, dehydroepiandrosterone and its sulfate, may regulate growth and function of peripheral target tissues, including the breast. Both endocrine and paracrine influences on the proliferation of human breast cancer cells are well recognized. Breast tumors harbor tumor-associated macrophages and tumor-infiltrating lymphocytes that secrete a wide spectrum of cytokines. These factors may also contribute to neoplastic cell activity. The present study was designed to investigate the action of cytokines on 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity, which is an essential step in the biosynthesis of active estrogens and androgens in human breast cancer cell lines and in normal human mammary epithelial cells in primary culture. 3Beta-HSD activity was undetectable in ZR-75-1 and T-47D estrogen receptor-positive (ER)+ cells under basal growth conditions. This activity was markedly induced after exposure to picomolar concentrations of interleukin (IL)-4 or IL-13. The potent stimulatory effect of these cytokines on 3beta-HSD activity was also observed in the ER- MDA-MB-231 human breast cancer cell line and in normal human mammary epithelial cells (HMECs) in primary culture. The stimulation of 3beta-HSD activity by IL-4 and IL-13 results from a rapid increase in 3beta-HSD type 1 mRNA levels as measured by RT-PCR and Northern blot analyses. Such an induction of the 3beta-HSD activity may modulate androgenic and estrogenic biological responses as demonstrated using ZR-75-1 cells transfected with androgen- or estrogen-sensitive reporter constructs and treated with the adrenal steroid 5-androstene-3beta,17beta-diol. The DNA-binding activity of Stat6, a member of the signal transducers and activators of transcription gene family, is activated 30 min after exposure to IL-4 and IL-13 in human breast cancer cell lines as well as in HMECs in primary culture. In these cells, Stat6 activated by IL-4 or IL-13 binds to two regions of the 3beta-HSD type 1 gene promoter, containing Stat6 consensus sequences. IL-4 induction of 3beta-HSD mRNA and activity is sensitive to staurosporine. This protein kinase inhibitor also inhibits IL-4-induced Stat6 DNA-binding activity. Our data demonstrate for the first time that IL-4 and IL-13 induce 3beta-HSD type 1 gene expression, thus suggesting their involvement in the fine control of sex steroid biosynthesis from adrenal steroid precursors in normal and tumoral human mammary cells. Furthermore, aromatase and/or 5alpha-reductase(s) are expressed in the mammary gland and in a large proportion of human breast tumors. An increase in the formation of their substrates, namely, 4-androstenedione and testosterone, may well have a significant impact on the synthesis of active estrogens and androgens in these tissues.
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PMID:Induction of 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and interleukin-13. 989 13

To determine the significance of interleukin (IL)-10 in antitumor immune response, the effect of the down-regulation of tumor-derived IL-10 on locoregional immunotherapy was investigated. C3H/HeN mice were intraperitoneally (i.p.) inoculated with IL-10-producing murine breast cancer cell line, FM3A, and treated with locoregional administration of OK-432 with or without anti-IL-10 monoclonal antibody (mAb). Anti-IL-10 mAb did not affect the in vitro growth of FM3A cells. Administration of OK-432 plus anti-IL-10 mAb remarkably delayed the retention of malignant ascites and prolonged the survival of mice compared with the administration of OK-432 alone. Spleen cells which were collected from mice treated with OK-432 plus anti-IL-10 mAb and further stimulated in vitro with inactivated FM3A cells exhibited significantly higher cytotoxicity against FM3A cells than those from mice treated with OK-432 alone or from the control mice. The expression of major histocompatibility complex (MHC) class II molecules on spleen cells was up-regulated in vitro by the addition of OK-432 and anti-IL-10 mAb. Using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), cytokine mRNA levels of peritoneal exudate cells (PEC) and spleen cells were assessed on day 7 (before treatment) and day 14 (after treatment). In PEC, increased expression of IL-2 was observed with the administration of OK-432 plus anti-IL-10 mAb. In spleen cells, the expression of IL-2, IL-12 and IFN-gamma were strongly induced, and IL-4 expression was reduced by the administration of OK-432 plus anti-IL-10 mAb. It is suggested that down-regulation of tumor-derived IL-10 induces the up-regulation of the T helper type (Th) 1 population, resulting in an enhancement of the efficacy of locoregional immunotherapy with OK-432.
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PMID:Down-regulation of IL-10 enhances the efficacy of locoregional immunotherapy using OK-432 against malignant effusion. 1036 57

The 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. In humans there are two 3beta-HSD isoenzymes, the type 1 gene being predominantly expressed in the placenta and peripheral tissues, whereas the type 2 gene is the predominant 3beta-HSD expressed in the adrenal glands and gonads. We have recently showed that interleukin (IL)-4 and IL-13 induce 3beta-HSD type 1 gene expression in human breast cancer cell lines as well as in normal human mammary epithelial cells. The present study was designed to investigate whether such a cytokine-induced 3beta-HSD type 1 expression would also be observed in cell types derived from other peripheral sex steroid target tissues. To gain further knowledge about the molecular mechanism of IL-4 action, we have studied whether the induction of 3beta-HSD type 1 expression in IL-4-responsive cell types would always be associated with the activation of Stat6, a member of the Signal Transducers and Activators of Transcription (STAT) gene family. Stat6 is recognized as the principal transcription factor mediating the effects of IL-4. In normal human prostate epithelial cells (PrEC), no 3beta-HSD activity was detectable under basal culture conditions, while exposure to IL-4 or IL-13 caused a potent induction of this activity. This effect results from a rapid induction of 3beta-HSD type 1 messenger RNA levels as determined by Northern blot and RT-PCR analyses. Furthermore, IL-4 and IL-13 also increased 3beta-HSD type 1 gene expression in human HaCaT immortalized keratinocytes, ME-180 cervix cancer cells, HT-29 colon cancer cells as well as in BT-20 and ZR-75-1 breast cancer cells. However, IL-4 and IL-13 failed to modulate the 3beta-HSD type 1 expression in human LnCAP and PC-3 prostate cancer cells, Caco-2 colon cancer cells as well as in JAR and JEG-3 choriocarcinoma cell lines. The DNA-binding activity of Stat6 was activated after a 30-min exposure to IL-4 in PrEC and in all the cell types where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. Our data therefore suggest that IL-4 and IL-13 may play a role in the biosynthesis of active sex steroids from the inactive adrenal steroid dehydroepiandrosterone, not only in breast cells but also in various cell types derived from peripheral target tissues, such as normal human prostate epithelial cells, immortalized keratinocytes, as well as colon and cervix cancer cell lines. Our data also demonstrates that the stimulatory effect of IL-4 was always associated with the activation of Stat6, thus supporting the essential role of Stat6 in this induction of 3beta-HSD type 1 gene expression.
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PMID:Induction of 3beta-hydroxysteroid dehydrogenase/isomerase type 1 expression by interleukin-4 in human normal prostate epithelial cells, immortalized keratinocytes, colon, and cervix cancer cell lines. 1049 13

Human breast cancer cells (OCUB-M), retrovirally transduced with granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-2 (IL-2) or IL-4 gene were examined for their antitumor activities in nude mice. Although cell proliferation rates in vitro of these cytokine-producing cells were not significantly different from that of wild-type cells, nude mice that were subcutaneously inoculated with cytokine-producing cells did not develop tumors in contrast to mice that were injected with wild-type cells. Injection of GM-CSF-producing cells into the vicinity of growing wild-type tumors retarded subsequent growth of wild-type tumors. Histological examination of tumors which received GM-CSF-producing cells revealed marked infiltration of mononuclear cells around the tumors. Irradiation of cytokine-producing cells diminished their proliferation capacity but production of cytokine(s) was retained. Therefore, inoculation of irradiated cytokine producer cells into growing tumors can be used as a therapeutic maneuver for breast cancer.
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PMID:Loss of tumorigenicity of human breast cancer cells engineered to produce IL-2, IL-4 or GM-CSF in nude mice. 1053 77


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