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

Retinoids and Interferons have been demonstrated to synergistically amplify the inhibition of proliferation in cultured breast cancer cells. Recently we reported that interferon-gamma (IFN-gamma) modulates the action of retinoic acid (RA): IFN-gamma increased expression of retinoic acid receptor-gamma (RAR-gamma) and suppressed the increase of retinoic acid binding protein type II (CRABP-II) expression. To improve the understanding of mechanism mediating synergism we extended our studies to the type I interferon-alpha. Synergistic inhibition of proliferation could be detected also by IFN-alpha and RA in BT-20 and SKBR-3 breast cancer cell lines but not in MCF-7 cells. Neither IFN-alpha nor any retinoid tested alone were able to increase RAR-gamma message, only the combination of both had this ability. In MCF-7 breast cancer cell lines the combination of any retinoid with IFN-alpha increased CRABP II expression level compared with the retinoids alone. In contrast with SKBR-3 and BT-20 cells a combination of ATRA with IFN-alpha markedly reduced ATRA mediated CRABP II induction. These results suggest that two factors may be responsible for synergistic action of RA and IFN-alpha: the inhibition of the CRABP II expression and an IFN-alpha/RA mediated upregulation of RAR-gamma.
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PMID:Interaction of retinoic acid and interferon-alpha in breast cancer cell lines. 861 38

The p185HER2 oncogene is associated with poor prognosis in patients with breast cancer. Both anti-p185HER2 MAb and cytokines have been shown to downregulate p185HER2 expression. We investigated the effect of combinations of humanized 4D5, and anti-p185HER2 MAB, and the cytokines IFN-alpha, IFN-gamma or TNF-alpha on the growth of three p185HER2 positive human abreast carcinoma cell lines, SK-BR-3, BT-474, and MDA-MB-453. All three cell lines were treated with IFN-alpha (1000 U/ml) or IFN-gamma (1000 U/ml) or TNF-alpha (100 U/ml) with or without huMAb 4D5 (100 microM), and cell growth was determined on days 3-7. While IFN-alpha, IFN-gamma, TNF-alpha, and huMAb 4D5 all inhibited growth, an apparently additive inhibitory effect occurred using combinations of huMAb 4D5 plus cytokine, with huMAb 4D5 plus TNF-alpha causing the greatest growth inhibition. These results demonstrate the potentiation of growth inhibition of breast cancer cell lines by the combination of anti p185HER2 MAb and cytokines, and suggest that combinations of anti-growth factor receptor MAb and cytokines may be useful in the treatment of breast cancer.
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PMID:Growth inhibition of breast cancer cell lines by combinations of anti-P185HER2 monoclonal antibody and cytokines. 861 49

Arginine-derived nitric oxide (NO) has been identified in some tumor cell lines and solid human tumors. The effect of tumor cell NO on tumor biology is poorly understood. The purpose of this study was to investigate the effect of NO production by EMT-6 murine breast cancer cells on tumor cell growth in vitro and subcutaneous tumor growth and experimental pulmonary metastasis in vivo. EMT-6 cells were incubated with endotoxin (LPS, 10 microgram/ml) and interferon-gamma (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, omega-nitro-L-arginine methyl ester (L-NAME, 2 mM), and NO production and cell number were assessed 24 hr later. EMT-6 cells were also treated overnight with LPS/IFN, in the presence or absence of L-NAME, washed and injected either subcutaneously in the dorsal flank (n = 40) or via the tail vein (n = 40) of syngeneic BALB/c mice. Two weeks following tumor cell injection, tumor size and number of pulmonary metastases were assessed. LPS/IFN stimulated NO production in EMT-6 cells and inhibited cell growth in vitro by 50%. L-NAME blocked LPS/IFN stimulation of NO production and restored cell growth to near control levels. When injected into BALB/c mice, LPS/IFN-stimulated tumor cells demonstrated a two-fold increase in subcutaneous tumor growth and experimental pulmonary metastases over control cells. L-NAME reduced tumor size and number of lung metastases to control levels, suggesting that tumor cell NO production was responsible for this effect. In summary, LPS/IFN-stimulated NO production in EMT-6 tumor cells inhibits tumor cell growth in vitro, yet paradoxically augments tumor growth and metastasis in vivo.
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PMID:Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo. 866 Nov 71

We investigated the effect of a concomitant treatment of ICI 164384 and B-interferon (beta-IFN) on the growth of estrogen-receptor-positive (ER+) and estrogen-receptor-negative (ER-) breast cancer cell lines and on their steroid receptor profiles. ICI 164384 reduced cell proliferation not only in ER+ but also in ER- cell lines and completely suppressed the stimulation induced by estradiol (E2) in hormone-sensitive cell lines, MCF7 and T47D. When associated with beta-IFN, ICI 164384 increased the inhibitory effect exerted by the low concentration of beta-IFN. Moreover, ICI 164384, singly or in association with beta-IFN, did not affect ER and PgR concentration in ER- cell lines, whereas in ER+ cell lines we observed an almost total disappearance of ER and PgR. In conclusion, our study seems to indicate that, although beta-IFN is able to control the proliferation of hormone-sensitive and hormone-independent subclones, it does not further improve the antiproliferative activity of ICI 164384. In contrast, the presence of ICI 164384, which does not induce the selection of resistant subclones under the same experimental conditions in which TAM does, may improve the efficacy of low concentration of beta-IFN and prevent the development of a secondary TAM-induced resistance.
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PMID:The effect of ICI 164384 and beta-interferon on the growth and steroid receptor profile of breast cancer cell lines. 866 23

Cytokine-based tumor antigen augmentation is one of the approaches researchers and clinicians are using to improve the effectiveness of MAb-directed tumor diagnosis and therapy. Other efforts encompass the use of dose-fractionation for multiple administrations of radioimmunoconjugates, exploitation of genetic engineering to construct antibody molecules with specific biological properties (i.e., altered pharmacokinetics, activation of cellular immune responses, etc.) and use of MAb-directed conjugates that can enhance tumor MAb uptake by altering tumor perfusion. The studies summarized here as well as those from other laboratories have served as the framework for clinical investigations designed to determine the effectiveness of the interferons and other differentiation-inducing agents to alter the tumor antigen phenotype in patients. In an earlier study, patients given IFN-alpha had improved tumor uptake of an antimelanoma MAb. Subsequently, we reported that i.p. IFN-gamma administration substantially upregulated TAG-72 and CEA on the surface of human tumor cells isolated from malignant ascites. A seminal investigation showed significant increase of TAG-72 and CEA levels in tumor biopsies from patients diagnosed with colorectal carcinoma and given systemic IFN-alpha. Those studies led to a clinical trial in which late stage breast cancer patients were administered interferon in combination with therapeutic doses of CC49. Some clinical responses were observed, however, the cytokine and MAb combination may have also enhanced marrow toxicity. Future studies will continue to evaluate the ability to enhance tumor antigen expression in the context of genetically engineered MAbs designed to minimize normal organ toxicity.
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PMID:Novel approaches to tumor detection and therapy using a combination of monoclonal antibody and cytokine. 869 32

CG-5 estrogen-sensitive human breast cancer cells contain specific Epidermal Growth Factor receptors (EGF-R, Kd = 0.09-0.17 nM) and respond to the mitogenic effect of EGF. The increase in cell proliferation has been observed starting with very low concentrations of EGF (10-12M) and was statistically significant at all doses. Nevertheless, cell growth stimulation was emphasized when cells were grown under stringent culture conditions. When cells were exposed to 100 IU/ml of natural beta-interferon (n beta-IFN) the binding of EGF to the cell membrane was reduced after 72 hours of treatment, while the exposure of CG-5 cells to 1000 IU/ml of n beta-IFN resulted in an EGF-R reduction which started after 48 hours and became statistically significant after 72-120 hours. If CG-5 cells were treated with 1000 IU/ml of recombinant alpha 2b-interferon (ra2b-IFN) this reduction was observed after 168 hours of exposure to the drug. Both the IFNs abolished EGF-stimulated cell growth. Our results indicate that IFN treatment down-regulates EGF-R in estrogen-sensitive breast cancer cells and suggests that this down-regulation may be involved in the inhibitory action of IFN on cell growth.
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PMID:Interferons inhibit EGF-stimulated cell growth and reduce EGF binding in human breast cancer cells. 871 21

It has been demonstrated, both in breast cancer cell lines and in metastatic breast cancer patients with cutaneous lesions that could be biopsied, that treatment with interferon beta (IFN-B) can increase expression of both estrogen (ER) and progesterone receptors (PgR). To evaluate the efficacy and toxicity of the combination of IFN and tamoxifen, 33 metastatic breast cancer patients were treated with the following regimen: IFN-B, 6.0 million units intramuscularly IU 3 times a week for two consecutive weeks followed by IFN-B 6.0 million IU im 3 times a week with concomitant tamoxifen 20 mg orally daily. Patients were pre and postmenopausal with median age of 60 years, median ECOG PS of 0, either ER positive or unknown, and had not received prior hormone therapy for metastatic disease. Overall objective response was observed in 9 (27%) patients. Complete response was observed in 2 cases and partial response in 7 patients. Median duration of response was 7 months (range 2-10). A higher response rate was observed in patients with predominantly soft tissue disease (38%) compared to patients with either dominant bone (18%) or visceral lesions (17%). Toxicity was mild and reversible: low grade fever in 30% of patients and flu-like symptoms in 9% of cases. It appears that IFN-B does not improve the efficacy of tamoxifen in an unselected population of metastatic breast cancer.
Breast Cancer Res Treat 1996
PMID:Tamoxifen and interferon-beta for the treatment of metastatic breast cancer. 887 32

The molecular basis for the enhanced growth inhibition of MCF-7 human breast cancer xenografts by a combination of human interferon-beta (IFN-beta) and tamoxifen was investigated. Treatment of MCF-7, MDA-MB-231, and BT-20 cells with the combination of IFN-beta and tamoxifen resulted in enhanced antiproliferative effects in vitro. Treatment with the combination of IFN-beta and tamoxifen enhanced the expression of several IFN-beta-inducible genes in human breast carcinoma cell lines relative to levels induced by IFN-beta alone. Tamoxifen alone did not induce transcription of IFN-stimulated genes (ISGs). Augmentation of ISG expression by the combination of IFN-beta and tamoxifen was noted in breast tumor cell lines irrespective of their functional estrogen receptor (ER) status or their dependence on estradiol for growth, suggesting that upregulation of ISGs was independent of ER status. Enhancement of IFN-stimulated gene expression by tamoxifen occurred at the transcriptional level. Expression of transfected reporter genes under the control of IFN-alpha/beta regulated promoters was also enhanced in IFN-beta and tamoxifen-treated cells. Similarly, transcriptional induction of chimeric reporter plasmids driven by an IFN-gamma inducible promoter (GAS; IFN-gamma activated site) was also enhanced by the combination of IFN-gamma and tamoxifen. In tamoxifen treated cells, IFN-beta and IFN-gamma readily activated transcription factors ISGF-3 and GAF, respectively. Therefore, augmentation of ISG expression by tamoxifen is an early event in the antitumoral activity of this drug combination.
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PMID:Tamoxifen enhances interferon-regulated gene expression in breast cancer cells. 905 94

Ex vivo genetically engineered cytokine-secreting tumor cell vaccines have been shown to prevent metastatic disease in animal models of lung and breast cancer. Because of the inefficiency of existing modes of gene delivery in transducing primary human tumor cells, it has been difficult to clinically apply this strategy. In this study, liposome-mediated delivery of an adeno-associated virus (AAV)-based plasmid containing the sequence for murine gamma-interferon (gamma-IFN) (pMP6A-mIFN-gamma) was used to generate cytokine-secreting murine tumor cell vaccines. High levels of gamma-IFN and elevated class I major histocompatibility complex expression after transfer of pMP6A-mIFN-gamma into the murine lung cancer cell line, D122, was demonstrated. The efficiency of gene transfer was determined by two different methods and was estimated to be 10-15%. Irradiated gamma-IFN D122 cells generated by this novel gene delivery system (D122/pMP6A-mIFN-gamma) and also by standard retroviral methods (DIF2) were administered as weekly vaccinations by intraperitoneal injection to animals bearing 7-day-old intrafootpad D122 tumors. Hindlimb amputation was performed when footpad diameters reached 7 mm, and lungs were harvested 28 days later. Animals vaccinated with gamma-IFN-secreting D122 cells produced by AAV-based plasmids delivery demonstrated a significant delay in footpad tumor growth when compared with controls and DIF2 cells. Fifty-seven percent of animals vaccinated with D122/pMP6A-mIFN-gamma were free of pulmonary metastases 28 days after amputation, significantly improved from the 0, 7, and 15% observed in animals vaccinated with irradiated parental D122 cells, irradiated D122 cells lipofected with an empty-cassette vector (pMP6A), or DIF2 cells, respectively. These results and the ability to transfer genes with this delivery system to a broad range of tumor types support its use in the generation of cytokine-secreting tumor cell vaccinations for use in clinical trials.
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PMID:Active immunization with tumor cells transduced by a novel AAV plasmid-based gene delivery system. 910 11

Type I interferons (IFN alpha and IFN beta) are presently used in the adjuvant treatment of several human cancers. However, these cytokines have demonstrated only modest success in breast cancer therapy, and research efforts have focused on improving their efficacy. Recent progress in understanding the molecular mechanisms underlying the antiproliferative effects of IFNs has identified the cytoplasmic transcription factor Stat1 as a critical mediator. It is, therefore, possible that IFN-induced growth inhibition of mammary epithelial cells is counteracted by other cytokines that also use Stat1. One such candidate IFN-antagonist with particular relevance to breast cancer is the mammotropic hormone prolactin (PRL). The main goal of this study was to examine whether PRL would interfere with type I IFN (IFN alpha/beta) signal transduction by competing for limited cytoplasmic Stat factors. A second aim was to test whether pretreatment of mammary tumor cell lines with IFN gamma could enhance the effect of IFN alpha/beta. By analyzing the effect of PRL on IFN alpha/beta-induced tyrosine phosphorylation of Stat proteins and their binding to IFN-regulated genes, we now report that costimulation of PRL receptors did not interfere with IFN alpha/beta signals in several human breast cancer cell lines, including T47D, MCF-7, and BT-20. Specifically, PRL did not affect IFN alpha/beta-induced tyrosine phosphorylation or heterodimerization of Stat1 and Stat2 in any cell line. Instead, IFN alpha/beta- and PRL-induced tyrosine phosphorylation of Stat1 was additive and occurred without evidence of competition for limited concentrations of cytoplasmic Stat1. A similar additive relationship was observed on IFN alpha/beta- and PRL-induced Stat3 tyrosine phosphorylation. Furthermore, electrophoretic mobility shift assays showed that type I IFNs induced predominantly Stat1-Stat2 or Stat1-Stat3 heteromeric complexes with various IFN-response elements of IFN-stimulated genes, whereas PRL induced Stat1 homodimers. Despite significant mutual use of Stats by IFNs and PRL, these results indicated a high degree of signaling specificity in the two receptor systems, and that cytoplasmic levels of Stat proteins were not limiting. Similarly, PRL did not interfere with the growth-inhibitory effect of IFN beta. On the other hand, the study indicated that pretreatment of human breast cancer cell lines with IFN gamma enhanced the growth-inhibitory action of type I IFNs, suggesting a possible avenue for improving the effect of type I IFNs in the treatment of breast cancer patients.
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PMID:Prolactin activates Stat1 but does not antagonize Stat1 activation and growth inhibition by type I interferons in human breast cancer cells. 958 33


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