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

The identification and characterization of tumor antigens has facilitated the development of immune-based cancer prophylaxis and therapy. Cancer vaccines, like viral vaccines, may be effective in cancer prevention. Adoptive T-cell therapy, in contrast, may be more efficacious for the eradication of existing malignancies. Our group is examining the feasibility of antigen-specific adoptive T-cell therapy for the treatment of established cancer in the HER2/neu model. Transgenic mice overexpressing rat neu in mammary tissue develop malignancy, histologically similar to human HER2/neu-overexpressing breast cancer. These mice can be effectively immunized against a challenge with neu-positive tumor cells. Adoptive transfer of neu-specific T cells into tumor-bearing mice eradicates malignancy. Effective T-cell therapy relies on optimization of the ex vivo expansion of antigen-specific T cells. Two important elements of ex vivo antigen-specific T-cell growth that have been identified are (1) the preexisting levels of antigen-specific T cells and (2) the cytokine milieu used during ex vivo expansion of the T cells. Phase I clinical trials of HER2/neu-based peptide vaccination in human cancer patients have demonstrated that increased levels of HER2/neu-specific T-cells can be elicited after active immunization. Initiating cultures with greater numbers of antigen-specific T cells facilitates expansion. In addition, cytokines, such as interleukin-12, when added during ex vivo culturing along with interleukin-2 can selectively expand antigen-specific T-cells. Interleukin-12 also enhances antigen-specific functional measurements such as interferon-gamma and tumor necrosis factor-alpha release. Refinements in ex vivo expansion techniques may greatly improve the feasibility of tumor-antigen T-cell-based therapy for the treatment of advanced-stage HER2/neu-overexpressing breast malignancy.
Clin Breast Cancer 2001 Apr
PMID:Expansion of HER2/neu-specific T cells ex vivo following immunization with a HER2/neu peptide-based vaccine. 1189 86

Interleukin (IL)-18 exhibits antitumor as well as antiosteoclastogenic activities. These findings suggest that IL-18 is a potential tool for the treatment of cancers with associated osteolytic bone metastasis. We have previously shown that systemic daily administration of recombinant (r) IL-18 inhibits the development of osteolytic bone metastasis by human breast cancer cells. Here we demonstrate that systemic daily administration of rIL-18 (1 microg/mouse/d) for 21 days significantly inhibited the number and the total area of osteolytic bone metastasis by RWGT2 human lung cancer cells in nude mice. No severe adverse effects were observed. Natural killer (NK) cells did not increase in splenocytes from rIL-18-treated mice, and the in vitro NK activity of splenocytes against RWGT2 cells was only weakly enhanced in the presence of IL-18. The administration of rIL-18 made no difference in the growth of subcutaneous tumors, histologic indices (mitotic index, apoptotic index, and Ki-67-labeling index) of subcutaneous tumors or metastatic bone foci, or in the number of osteoclasts along the bone surface adjacent to tumors. Moreover, serum levels of cytokines including interferon-gamma, IL-1alpha, IL-6, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor, which regulate bone-resorbing activity of osteoclasts, were evaluated. Among them, IL-6 was remarkably downregulated in rIL-18-treated mice. These findings suggest that IL-18 inhibits osteolytic bone metastasis possibly through suppression of osteoclastic bone-resorption mediated in part by IL-6.
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PMID:Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice. 1204 51

Biological therapies are new additions to breast cancer treatment. Among biological compounds, beta-carotene has been reported to have immune modulatory effects, in particular, enhancement of natural killer cell activity and tumor necrosis factor-alpha production by macrophages. The objective of this study was to investigate the effect of palm carotene supplementation on the tumorigenicity of MCF-7 human breast cancer cells injected into athymic nude mice and to explore the mechanism by which palm carotenes suppress tumorigenesis. Forty-eight 4-wk-old mice were injected with 1 x 10(6) MCF-7 cells into their mammary fat pad. The experimental group was supplemented with palm carotene whereas the control group was not. Significant differences were observed in tumor incidence (P< 0.001) and tumor surface area and metastasis to lung (P< 0.005) between the two groups. Natural killer (NK) cells and B-lymphocytes in the peripheral blood of carotene-supplemented mice were significantly increased (P < 0.05 and P < 0.001, respectively) compared with controls. These results suggest that palm oil carotene is able to modulate the immune system by increasing peripheral blood NK cells and B-lymphocytes and suppress the growth of MCF-7 human breast cancer cells.
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PMID:Effect of palm oil carotene on breast cancer tumorigenicity in nude mice. 1212 Sep 53

Neutralization of endogenous growth factors and administration of exogenous bioactive cytokines are two distinct biological antitumor strategies that show promise for treatment of cancer patients. In this report, we provide evidence to link both strategies as an integrative approach to cancer therapy. We tested the hypothesis that proinflammatory cytokines block growth of transformed cells by inhibiting key intracellular signaling events after activation of the insulin-like growth factor-I (IGF-I) tyrosine kinase receptor. IGF-I stimulates DNA synthesis in MCF-7 cells by 15-fold. This increase is significantly inhibited by TNF (tumor necrosis factor) -alpha at 0.1 ng/ml and is reduced by 80% at 100 ng/ml. Similarly, both IL (interleukin) -1beta and IL-6 significantly reduce the ability of IGF-I to promote DNA synthesis. Flow cytometry confirmed that all three of the cytokines inhibit IGF-I-induced DNA synthesis by preventing cells from entering the S phase of the cell cycle, leading to G(0)/G(1) arrest. Although none of the cytokines alone are cytotoxic to transformed epithelial cells in the absence of serum, TNF-alpha significantly inhibits the antiapoptotic property of IGF-I in protecting MCF-7 cells from DNA fragmentation. TNF-alpha and IL-1beta act by inhibiting the IGF-I receptor from tyrosine phosphorylating insulin receptor substrate-1 without affecting tyrosine kinase activity of the IGF-IR itself. These data support the novel idea that the major inhibitory properties of proinflammatory cytokines on growth of breast cancer cells are manifested prominently in the presence of growth factors. These data also highlight growth factor receptor adaptor molecules, such as insulin receptor substrate-1, rather than the receptors themselves as targets for antitumor therapeutic strategies.
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PMID:Proinflammatory cytokines block growth of breast cancer cells by impairing signals from a growth factor receptor. 1218 34

Several cytokines including members of the transforming growth factor-beta (TGF-beta) and tumor necrosis factor (TNF) families have been implicated in the homing mechanism of breast cancer metastasis. We hypothesize that primary breast tumor tissues differentially express modulators of bone cell function and that this expression pattern contributes to their aggressive and metastatic potential and to their capacity to establish and grow in bone. We, therefore, examined the gene expression pattern of the TGF-beta family members (inhibin/activin betaA subunit (activin betaA), inhibin alpha subunit, and bone morphogenetic protein-2 (BMP-2)), the TNF family members (receptor activator of NF-KB ligand (RANKL) and osteoprotegerin (OPG)), and osteopontin (OPN) in normal, non-invasive, invasive, and metastatic human breast cancer specimens. The mRNA transcript levels of these genes were quantified by reverse transcription (RT) and fluorescent-based kinetic PCR in 18 normal breast tissues, five ductal carcinoma in situ (DCIS). 24 primary breast tumor tissue, and five distant metastases. The mRNA transcript level of each gene was normalized to the amount of beta-actin present in the samples. We observed differential gene expression of the selected TGF-beta family members as well as OPN in breast cancer progression. The average gene expression of the putative tumor suppressor, inhibin alpha, did not significantly change in any of the tumor tissues examined compared to normal breast tissue. The mRNA level of BMP-2, a protein with anti-proliferative effects in breast cancer cell lines and involved in bone formation, significantly decreased in non-invasive, invasive, and liver metastatic breast tumor tissue compared to normal breast tissue. The gene expression of activin betaA, a protein involved in cell proliferation and osteoclast induction, increased in invasive and bone metastatic tumor tissue compared to normal breast tissue. The mRNA level of OPN, a bone matrix protein associated with enhanced malignancy, increased in non-invasive, invasive, and liver and bone metastatic breast tumor tissue compared to normal breast tissue. In contrast, the average gene expressions of the TNF family members, RANKL and OPG, proteins involved in the regulation of osteoclastogenesis, were only slightly if at all changed in the different stage breast tumor tissues. These results suggest that differential gene expression of bone-related proteins, especially OPN, activin betaA, and BMP-2, by primary breast tumor tissues may play a significant role in the invasiveness and metastatic potential of breast cancer.
Breast Cancer Res Treat 2002 Jun
PMID:Differential gene expression of TGF-beta family members and osteopontin in breast tumor tissue: analysis by real-time quantitative PCR. 1220 15

The MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancers. Persistent stimulation by proinflammatory cytokines may contribute to increased MUC1 transcription by tumor cells. We demonstrate that MUC1 expression in T47D breast cancer cells and normal human mammary epithelial cells (HMEC) is enhanced by tumor necrosis factor-alpha (TNF-alpha) in the presence of interferon-gamma (IFN-gamma). MUC1 responsiveness to these cytokines was modest in T47D cells and robustly induced in HMEC. Transient transfection of T47D cells with mutant MUC1 promoter constructs revealed that a kappaB site at -589/-580 and the STAT-binding element at -503/-495 and were required for cooperative stimulation by TNFalpha and IFN-gamma. Binding of NFkappaB p65 to the MUC1 kappaB site was induced by TNF-alpha treatment, as demonstrated by electrophoretic mobility shift assay. Specific mutation of the kappaB site prevented binding of NFkappaB p65 and blocked TNF-alpha stimulation of MUC1 promoter activity. Collectively, these studies demonstrate synergistic stimulation of MUC1 expression by TNF-alpha and IFN-gamma that is mediated by independent actions of NFkappaB p65 and STAT1alpha upon kappaB and STAT sites, respectively, in the MUC1 promoter. Strong induction of MUC1 expression by these proinflammatory cytokines is clearly evident in normal mammary epithelium. In contrast, breast tumor cells appear to override normal regulatory responses via as yet undefined cis-elements.
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PMID:Synergistic stimulation of MUC1 expression in normal breast epithelia and breast cancer cells by interferon-gamma and tumor necrosis factor-alpha. 1221 Jul 42

The chromosome region 8p12-p22 shows frequent allelic loss in a variety of human malignancies, including breast cancer (BC). The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptors TRAIL-R1, -R2, -R3 and -R4 are located on 8p21-p22 and might be candidate tumor suppressor genes in this region. To evaluate the involvement of TRAIL receptors in breast carcinogenesis, we have analyzed the entire coding region of TRAIL-R2 and the death domain (DD) regions of TRAIL-R1 and -R4 for the detection of somatic mutations in a series of breast tumors, lymph node metastases and BC cell lines. Overall, we detected 1, 11 and 3 alterations in the TRAIL-R1, -R2 and -R4 genes, respectively. Although functional studies have not yet been performed, we assume that most of these alterations do not alter the function of TRAIL-receptors. Additionally, we analyzed individuals from BC families for the detection of TRAIL-R2 germline mutations. One alteration has been found in the Kozak consensus motif at position -4 with respect to the translation initiation AUG [1-4 (C-->A)]. We further studied the mRNA expression of TRAIL and the 4 TRAIL receptors. In BC cell lines, a strongly decreased mRNA expression of TRAIL, TRAIL-R1, -R3 and -R4 was found, whereas the expression of TRAIL-R2 was only slightly reduced. In breast tumors, a 1.2-3.6-fold reduction of mRNA signals of the 5 genes was observed. No correlation was found between the expression level of TRAIL and the receptor mRNAs and clinicopathologic variables and between the expression of TRAIL-R2 and TP53 mutation status and loss of heterozygosity (LOH) at 8p21-p22. Taken together, we cannot exclude the involvement of TRAIL-receptors in BC. Our mutation studies indicate that DD receptor mutations occur at low frequency and are not the primary cause for the altered mRNA expression of TRAIL and TRAIL-receptors in BC.
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PMID:Mutation analysis and mRNA expression of trail-receptors in human breast cancer. 1238 6

The Her-2/neu oncogene, the second member of the epidermal growth factor (EGF) receptor family, encodes a transmembrane tyrosine kinase receptor. Overexpression of Her-2/neu in approximately 30% of breast cancers is associated with poor overall survival. Recently, we have found that Her-2/neu activates nuclear factor (NF)-kappaB via a phosphatidylinositol 3 kinase (PI3-K)-Akt kinase signaling pathway in mouse mammary tumor virus (MMTV)-Her-2/neu NF639 mouse breast cancer cells. Surprisingly, the IkappaB kinase (IKK) kinase complex, implicated in proteasome-mediated degradation of IkappaB-alpha and activation of NF-kappaB via the canonical pathway, was not activated in these cells. Degradation of IkappaB-alpha was mediated via calpain, which in B cells is facilitated by phosphorylation of IkappaB-alpha by the protein kinase CK2. Here, we report that the inhibition of CK2 blocks Her-2/neu-mediated activation of NF-kappaB. NF639 breast cancer cells, stably expressing CK2alpha or CK2alpha' kinase-inactive mutants, displayed decreased NF-kappaB binding and reduced ability to grow in soft agar, as well as increased sensitivity to tumor necrosis factor (TNF)-alpha killing. Similarly, CK2 kinase-inactive subunits inhibited NF-kappaB activity in Hs578T human breast cancer cells, which also display elevated CK2 activity. In NIH 3T3 fibroblasts, which express low basal NF-kappaB and CK2 activities, overexpression of CK2 by retroviral gene delivery led to increased IkappaB-alpha turnover and the induction of classical NF-kappaB (p50/RelA). Thus, CK2 plays an important role in Her-2/neu signaling, promoting IkappaB-alpha degradation and, thereby, NF-kappaB activation. Furthermore, because ectopic CK2 activity appears sufficient to induce NF-kappaB, the elevated CK2 activity observed in many primary human breast cancers likely plays a role in aberrant activation of NF-kappaB and, therefore, represents a potential therapeutic target.
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PMID:Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. 1243 79

Vascular endothelial growth factor C (VEGF-C) is a critical activator of tumor lymphangiogenesis that recently has been strongly implicated in the tumor metastasis process. In this study, we identified that HRG-beta 1 stimulated up-regulation of VEGF-C mRNA and protein of human breast cancer cells in a dosage- and time-dependent manner and that this up-regulation was de novo RNA synthesis-dependent. The HRG-beta 1-induced increase in VEGF-C expression was effectively reduced by treatment with Herceptin, an antibody specifically against HER2. Also, when HER2 was overexpressed in MCF-7 cells that resulted in an evident increase in the VEGF-C level, suggesting an essential role of HER2 in mediating VEGF-C up-regulation by HRG-beta 1. NF-kappa B has been shown to be probably involved in interleukin-1 beta- or tumor necrosis factor-alpha-induced VEGF-C mRNA expression in human fibroblasts. Here we found that HRG-beta 1 could stimulate NF-kappa B nuclear translocation and DNA-binding activity via the I kappa B alpha phosphorylation-degradation mechanism. Blockage of the NF-kappa B activation cascade caused a complete inhibition of the HRG-beta 1-induced elevation of VEGF-C. In promoter-reporter assay, the luciferase activities of the reporter constructs, including the putative NF-kappa B site deleted and mutated form were significantly reduced after HRG-beta 1 treatment as compared with the 1.5-kb VEGF-C promoter. Although investigating the upstream kinase pathway(s) involved in HRG-beta 1-elicited NF-kappa B activation and VEGF-C up-regulation, we found that HRG-beta1 could activate extracellular signal-regulated protein kinase 1/2, phosphatidylinositol 3'-kinase, and p38 mitogen-activated protein kinase (MAPK) in MCF-7. However, only SB203580 (a specific inhibitor of p38 MAPK), not PD98059 nor LY294002, blocked the up-regulation of VEGF-C by HRG-beta 1. A similar inhibition in VEGF-C expression was obtained by cell transfection with dominant-negative p38 (p38AF). Interestingly, the HRG-beta 1-induced NF-kappa B activation cascade was also effectively blocked by SB203580 treatment or p38AF transfection. Our data thus suggests that HRG-beta 1 stimulated a NF-kappa B-dependent up-regulation of VEGF-C through the p38 MAPK signaling pathway in human breast cancer cells.
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PMID:Up-regulation of vascular endothelial growth factor C in breast cancer cells by heregulin-beta 1. A critical role of p38/nuclear factor-kappa B signaling pathway. 1247 Oct 41

N-(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer. Apoptotic agents, such as phorbol ester, tumor necrosis factor-alpha, and peptide hormones, have been shown to increase NO production in breast cancer cells. Therefore, we hypothesized that the production of No is vital for 4-HPR to induce apoptosis in breast cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced. To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), and 4-HPR, L-NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both IFN-gamma and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with 4-HPR, IFN-gamma and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis in breast cancer cells, i.e., by increasing NOS expression to induce NO production.
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PMID:A novel mechanism by which N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell growth: the production of nitric oxide. 1248 23


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