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

We compared tumor necrosis factor (TNF) metabolism by wild-type MCF-7 (WT) cells, by 40-fold doxorubicin resistant (40F) breast cancer cells and by PC3 and LNCaP prostate cancer cell lines. MCF-7 WT and LNCaP cell lines were sensitive to TNF cytotoxicity and both lines produced two major intracellular TNF degradation products of 15 kDa and 5.5 kDa. The MCF-7 40F and the PC3 cell lines were resistant to TNF and produced multiple TNF degradation products with molecular weights lower than 15 kDa. Both the breast and prostate lines showed TNF receptor crosslinking patterns consistent with a molecular weight of 55 kDa. The breast and LNCaP lines expressed TNF receptors with an apparent dissociation constant (Kd) of 0.4 to 0.6 nM, while the TNF resistant line had a Kd of 2 nM. Similar receptor numbers per cell were found for all cell types (4,000 to 8,000/cell), and comparable levels of TNF internalization were noted. TNF-conditioned medium from the TNF-sensitive cell types was cytotoxic toward both the TNF-sensitive and TNF-resistant lines, and the toxicity was significantly blocked by an anti-TNF monoclonal antibody. Hydrophobic interaction column HPLC fractionation of the TNF-degradation products produced by MCF-7 WT and LNCaP cells revealed that the trimeric, monomeric, and 5.5 kDa fractions possessed the greatest in vitro antitumor activity. These findings suggest that a TNF degradation product, produced selectively by TNF-sensitive cells, may contribute to the antitumor action of TNF.
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PMID:Selective formation of tumor necrosis factor-alpha (TNF) degradation products contributes to TNF mediated cytotoxicity. 131 75

Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor on U937 cells results in rapid and TNF dose-dependent phosphorylation of a cytosolic protein with an apparent molecular mass of 26,000 kDa (p26) and an isoelectric point of 5.6. Half-maximal phosphorylation of p26 was achieved at concentrations of 1.8 ng/ml and was detectable within 20 s of TNF-alpha treatment. p26 is phosphorylated exclusively at serine residues. p26 phosphorylation occurs at 37 degrees C as well as at 14 degrees C, indicating that internalization of the TNF receptor is not required for serine kinase activation. Dephosphorylation of p26 starts 10 min after TNF-induced phosphorylation, suggesting a possible regulatory function of this cytosolic protein within the post-TNF receptor signaling system. p26 is also phosphorylated upon treatment with lymphotoxin. In contrast, both interferon-gamma and lipopolysaccharide fail to induce p26 phosphorylation. Whereas phosphorylated p26 was detected in the TNF-sensitive breast cancer cell line CRL1500, other TNF-responsive tumor cell lines investigated lacked enhanced phosphorylation of p26 in response to TNF, indicating that the 26-kDa phosphoprotein (pp26) may be a cell type-specific second messenger molecule involved in TNF signal transduction in some, but not all, target cells. p26 is also phosphorylated in a subclone of U937 (U937.C27) that responds to TNF-alpha with differentiation, yet is resistant to TNF-alpha-mediated growth inhibition. In contrast, p26 is not phosphorylated in another U937 derivative (U937.G3) that is resistant to both TNF-alpha-induced growth arrest and differentiation, suggesting that pp26 may play a role in the TNF signaling pathway linked to differentiation processes rather than to growth control.
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PMID:Tumor necrosis factor signal transduction. Tissue-specific serine phosphorylation of a 26-kDa cytosolic protein. 253 51

The aim of this study was to investigate mechanisms of anti-tumour activity and necrosis induced by combinations of tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). In a breast cancer xenograft model, locally injected recombinant human TNF-alpha arrested growth of established tumours in the absence of overt necrosis. Macroscopic necrosis occurred when rat IFN-gamma, which had no anti-tumour activity as a single agent, was given systemically. Treatment with TNF-alpha and IFN-gamma caused focal engorgement of tumour capillaries with erythrocytes, intravascular recruitment of polymorphonuclear cells and platelet adherence to the tumour vascular endothelium 4 h after the combined treatment. This was followed by destruction of tumour vascular endothelium and both necrosis and apoptosis of tumour cells. Concomitant with these changes, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed the increase of stromal (murine) mRNA levels for TNF-alpha, TNF receptor 55 kDa, TNF receptor 75 kDa, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, P-selectin and interleukin 6 (IL-6). Thus, the effect of the combined TNF-alpha and IFN-gamma therapy involved the selective destruction of the tumour vasculature, death of tumour cells and increased expression of a series of stromal cytokines, cytokine receptors and adhesion molecules, which could be implicated in the observed events.
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PMID:Changes in endogenous cytokines, adhesion molecules and platelets during cytokine-induced tumour necrosis. 757 63

The response of human T lymphocytes to various stimuli includes the expression of the matrix metalloproteinase (MMP) genes stromelysin 2, gelatinase A and gelatinase B. The proteins encoded by these genes could confer the capacity to degrade macromolecular components of the extracellular matrix (ECM), and to shed transmembrane proteins such as tumor necrosis factor (TNF), TNF receptor, Interleukin-6 receptor and Fas ligand. To identify further MMP genes transcribed in T lymphocytes exposed to phorbol 12-myristate 13-acetate and a calcium ionophore, we combined reverse transcription and polymerase chain reaction using primers specific for conserved domains and detected collagenase 3 transcripts, first described in a human breast cancer. However, when the sequence of the complementary DNA was compared, additional 23 nucleotides were found in the 5' nontranslated region of the lymphocyte messenger RNA (mRNA). Northern blot analysis revealed 2 major inducible mRNA species of 1.9 and 2.8 kilobases, whose levels were lower than those of stromelysin 2. The observation that activated T lymphocytes transcribe several MMP genes, including a collagenase, indicates that the effector functions of these cells include enzymatic activities towards most constituents of the ECM, as well as some transmembrane proteins relevant to inflammation and apoptosis.
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PMID:A matrix metalloproteinase gene expressed in human T lymphocytes is identical with collagenase 3 from breast carcinomas. 956 63

The CD40 molecule, a member of the TNF receptor gene family, has been intensively studied with respect to regulation of B cell proliferation and survival. Although CD40 is also expressed on carcinoma cell lines, information concerning the biological function of CD40 on cells of epithelial origin is limited. In this study we detected constitutive CD40 on human breast carcinoma cell lines and an increase in CD40 expression following treatment with cytokines IL-1alpha and IFN-gamma. CD40 ligation was also found to increase MHC II expression in cells pretreated with IFN-gamma. In contrast to normal B cells, where CD40 signaling provides a potent survival signal, we observed that CD40 ligation in breast carcinoma cells results in growth inhibition and enhanced susceptibility to Fas-mediated apoptosis. Enhanced apoptosis appears to be attributable, at least in part, to an up-regulation of Fas expression caused by CD40 ligation. These results suggest a potentially important role for CD40 in breast tumor biology.
Breast Cancer Res Treat 1998 Jul
PMID:CD40 is functionally expressed on human breast carcinomas: variable inducibility by cytokines and enhancement of Fas-mediated apoptosis. 980 17

The toxic effects of tumor necrosis factor alpha (TNFalpha) have greatly limited its use in tumor therapy. Recently, clear evidence has been obtained linking the p55 TNF receptor (TNFR) to the induction of systemic toxicity. We have generated a p75 murine TNFR (mTNFR)-specific mutant of mTNFalpha (D142N-A144R), cloned this gene into a recombinant adenovirus vector (Ad-75), and studied its efficacy for tumor immunotherapy of a murine transgenic breast cancer model. Cell culture supernatants from Ad-75-transduced cells showed no cytotoxic activity on L929 cells, but retained the ability to induce proliferation of a murine T-cell line (CT6); this activity was not blocked by soluble p55 mTNFR. Furthermore, it was shown that the mutant form of mTNFalpha was able to coimmunoprecipitate only with the p75 mTNFR and not with the p55 mTNFR. Tumors injected with Ad-75 became necrotic, and mice injected with < or =1 x 10(9) plaque-forming units showed no mortality, whereas both wild-type murine and human TNF vectors induced lethality at doses of 1 and 5 x 10(8) plaque-forming units. All Ad-TNF vectors induced partial or permanent tumor regressions, with cured mice showing immune memory against the tumor. These results demonstrate that a p75 mTNFR agonist expressed from a recombinant adenovirus vector does not induce mortality at doses that cause tumor regression.
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PMID:A p75 tumor necrosis factor receptor-specific mutant of murine tumor necrosis factor alpha expressed from an adenovirus vector induces an antitumor response with reduced toxicity. 1050 57

Ceramide, as a second messenger, initiates one of the major signal transduction pathways in tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. Glucosylceramide synthase (GCS) catalyzes glycosylation of ceramide and produces glucosylceramide. By introduction of the GCS gene, cytotoxic resistance to TNF-alpha has been conferred in human breast cancer cells. MCF-7/GCS-transfected cells expressed 4.1-fold higher levels of GCS activity and exhibited a 15-fold (P < 0.0005) greater EC(50) for TNF-alpha, compared with the parental MCF-7 cell line. DNA fragmentation and DNA synthesis studies showed that TNF-alpha had little influence on the induction of apoptosis or on growth arrest in MCF-7/GCS cells, compared to MCF-7 cells. These studies reveal that TNF-alpha resistance in MCF-7/GCS cells is closely related to ceramide hyperglycosylation, a hallmark of this transfected cell line, and resistance was not aligned with changes in TNF receptor 1 expression. This work demonstrates that GCS, which catalyzes ceramide glycosylation, potentiates cytotoxic resistance to TNF-alpha.
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PMID:Glycosylation of ceramide potentiates cellular resistance to tumor necrosis factor-alpha-induced apoptosis. 1052 36

The active form of vitamin D(3), 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), induces caspase-independent apoptosis in MCF-7 and T47D breast cancer cells. Before the appearance of apoptotic cells at Day 4 after the addition of 1,25(OH)(2)D(3), the MCF-7 cells are sensitized to the caspase-mediated apoptosis induced by TNF. We studied the mechanism underlying the cross talk between these 2 distinct death pathways in MCF-7 and T47D cells. Whereas 1,25(OH)(2)D(3) pre-treatment enhanced TNF-induced apoptosis of TNF sensitive MCF-7 cells, it failed to render TNF resistant T47D cells sensitive to this cytokine. Opposing to an earlier report suggesting that cytosolic phospholipase A(2) (cPLA(2)) mediates the 1,25(OH)(2)D(3)-induced sensitization to TNF, we could not detect any cPLA(2) protein in MCF-7 cells and its overexpression had no effect on cellular sensitivity to 1,25(OH)(2)D(3) or the combination with TNF. The sensitization of MCF-7 cells to TNF-induced apoptosis by pre-treatment with 1,25(OH)(2)D(3) may instead be partially explained by an increased surface expression of the TNF receptor 1 (TNF-R1). In line with this, not only the TNF-induced activation of caspases and apoptosis but also that of NF-kappaB was enhanced by 1,25(OH)(2)D(3) pre-treatment. Furthermore, 1,25(OH)(2)D(3) enhanced TNF-induced NF-kappaB activation in T47D cells suggesting that it potentiates TNF signaling in general. Interestingly, the lysosomal protease cathepsin B, which expression is up-regulated by 1,25(OH)(2)D(3), was released from the lysosomes upon TNF treatment, and inhibition of its activity rescued 1,25(OH)(2)D(3) treated MCF-7 cells from TNF-induced apoptosis. In conclusion, 1,25(OH)(2)D(3) may enhance TNF-induced apoptosis by increasing the expression of both the TNF-R1 and cathepsin B.
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PMID:Sensitization to TNF-induced apoptosis by 1,25-dihydroxy vitamin D(3) involves up-regulation of the TNF receptor 1 and cathepsin B. 1141 Aug 70

Overexpression of HER-2/neu confers cellular resistance to tumor necrosis factor (TNF)-mediated cytotoxicity to SKBR-3 breast cancer cell lines. To understand the correlation between HER-2/neu expression and TNF resistance, we examined the unique signaling pathways associated with the cytotoxic effects of the immunocytokine scFv23/TNF, recombinant single-chain antibody fusion constructs containing TNF and targeting HER-2/neu, in TNF-resistant SKBR-3-LP cells. We found that treatment of HER-2/neu-overexpressing SKBR-3-LP cells with scFv23/TNF resulted in a 5- to 7-fold higher level of TNF receptor-1 expression 48 hours after exposure. In addition, treatment of SKBR-3-LP cells with scFv23/TNF resulted in down-regulation of Akt phosphorylation and induced apoptosis through cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase. ScFv23/TNF-induced cytotoxicity was inhibited by blocking of the binding of the TNF component of scFv23/TNF to TNF receptor-1 and was dependent on activation of caspase-8 and caspase-3. These results indicate that the immunocytokine scFv23/TNF sensitizes TNF-resistant HER-2/neu-overexpressing SKBR-3-LP cells to TNF-induced apoptosis via the overexpression of TNF receptor-1 and suggest that the overexpression of TNF receptor-1 plays a crucial role in TNF sensitivity in HER-2/neu-overexpressing cancer cells. ScFv23/TNF targeting the HER-2/neu may be an effective cytotoxic agent against HER-2/neu-overexpressing cancer cells, which are inherently resistant to TNF.
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PMID:The immunocytokine scFv23/TNF sensitizes HER-2/neu-overexpressing SKBR-3 cells to tumor necrosis factor (TNF) via up-regulation of TNF receptor-1. 1609 36

Human activation-inducible TNF receptor (AITR) is a new member of the tumor necrosis factor family and expressed on peripheral blood mononuclear cells (PBMC) and leukocytes. Its ligand (AITRL) is expressed in endothelial cells. This study aimed to evaluate the presence and role of AITR and AITRL in patients with breast cancer. Expression of AITR and AITRL on PBMC and breast cancer cells was determined by flow cytometry, RT-PCR and fluorescence microscopy. Soluble (s) AITR and sAITRL were detected in serum of breast cancer patients by ELISA. AITR and AITRL were constitutively expressed in T cells, B cells, monocytes and monocyte-derived dendritic cells of breast cancer patients. AITRL was overexpressed in breast cancer cells. The levels of sAITRL were significantly increased in serum of breast cancer patients compared with the healthy control. This study suggests that AITR and AITRL may play an important role in tumor growth and survival in breast cancer.
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PMID:Expression of AITR and AITR ligand in breast cancer patients. 1791 71


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