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)

Prolactin (PRL) has been reported to inhibit apoptosis in various cell types and to serve as a cofactor in the upregulation of CD25 on T cells during activation. We investigated a possible relation between prolactin receptor (PRL-R) or IL-2 receptor alpha (IL-2Ralpha, CD25) expression on circulating T lymphocytes and their apoptosis in patients with breast cancer. Peripheral blood mononuclear cells obtained from 25 patients, 25 normal controls (NC) and three cord blood samples were evaluated for Annexin V binding and expression of CD95, CD25, and PRL-R on CD3(+) T cells by multicolour flow cytometry. Plasma levels of PRL, sCD95L, and sIL-2R were determined in patients and controls and related to T-cell apoptosis. The ability of PRL to protect T cells from apoptosis induced by various agents was also studied. Expression of PRL-R on the surface of T cells was comparable in patients with breast cancer and NC, but PRL plasma levels in patients were significantly lower (P<0.05). In patients, 18+/-11% (mean+/-s.d.) of CD3(+) cells bound Annexin V, compared to 9+/-6% in NC (P<0.0004). Percentages of CD3(+)Fas(+) and CD3(+)CD25(+) cells were higher in the peripheral circulation of patients than NC (P<0.0001 and <0.04, respectively). Levels of sFasL were lowest in plasma of the patients with the highest proportions of CD3(+)Fas(+) T cells. Most T cells undergoing apoptosis were CD3(+)CD25(-) in patients, and the proportion of CD3(+)CD25(-) Annexin V(+) cells was significantly increased in patients compared to NC (P<0.006). Ex vivo PRL protected T cells from starvation-induced or anti-CD3Ab-induced but not from Fas/FasL-dependent apoptosis. These results indicate that expression of CD25 but not of PRL-R on the surface of activated T lymphocytes appears to be involved in modulating Fas/Fas - ligand interactions, which are, in part, responsible for apoptosis of T lymphocytes and excessive turnover of immune cells in the circulation of patients with breast cancer.
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PMID:Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer. 1269

Breast cancer (BCA) represents the highest incidence of death in 35- to 60-year-old women. Above all, hormone unresponsive BCA is still associated with poorer prognosis than hormone receptor expressing malign, mammary tumors. There is a consistent need for effective compounds to treat especially the first variant of this disease. Therefore, we investigated the cytotoxic effects of the marine polyether triterpenoid dehydrothyrsiferol (DT) in four BCA cell lines. Annexin V labeling revealed higher rates of DT-induced apoptosis in hormone insensitive than in estrogen receptor expressing cells. Flow cytometric analysis of combined DNA fragmentation and total DNA labeling allowed us to ascribe apoptotic cells to their cell cycle stage. Although, high cell mortality was detected in mitogen dependent G(1)-phase, time, concentration, and cell line dependent populations of apoptotic cells were also found to be of S-phase and G(2)/M-phase origin. These results suggest that the induction of apoptosis by DT might be transduced through more than one effector pathway. Cell cycle distributions and 5-bromo-2'-deoxyuridine incorporation varied in a treatment dependent manner and differed from control experiments with colchicine and doxorubicin which exclude that DT functions as a mitosis inhibitor. In summary, we propose that DT might be an interesting candidate for an antitumor drug development regimen.
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PMID:Induction of apoptosis in estrogen dependent and independent breast cancer cells by the marine terpenoid dehydrothyrsiferol. 1273 57

The gef gene has cell-killing functions in Escherichia coli. To evaluate the feasibility of using this gene as a new strategy for cancer therapy, we transfected it in MCF-7 cells derived from breast cancer (MCF-7TG). The gef gene was cloned in a pMAMneo vector under the control of a mouse mammary tumour virus promoter, inducible by dexamethasone (Dex), and was transfected with liposomes. After selection and induction, expression of the gef gene was confirmed by reverse transcription-polymerase chain reactions (RT-PCR) and Western blot. Cell viability was determined with a haemocytometre and the sulphorodamine B colorimetric assay, and the cell cycle was studied by propidium iodide (PI) staining. Annexin V-FITC and PI assays were used to evaluate apoptosis, which was confirmed by electron microscopy. In comparison with MCF-7 parental cells and MCF-7 cells transfected with an empty vector, MCF-7TG cells induced with Dex showed a significant decrease in proliferation rate, which was associated with evidence of apoptosis. Morphological findings confirmed apoptosis and showed a typical pattern of mitochondrial dilation. Furthermore, the cell cycle was characterised by premature progression from G(1) to S phase and G(2) delay. Our results show that the gef gene was able to decrease proliferation in a breast cancer cell line, and induce apoptosis. These findings suggest that the gef gene is a potential candidate for tumour therapy.
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PMID:Inhibition of growth and induction of apoptosis in human breast cancer by transfection of gef gene. 1283 23

Members of the ABC (ATP-binding cassette) transporter super-family are emerging to be involved in lipid transport. In the present study, we studied the organization of phospholipids in the plasma membrane of EPG85-257 human gastric carcinoma cells overexpressing BCRP (breast cancer resistance protein, ABCG-2), a half-size transporter belonging to the ABCG subfamily. A significantly increased plasma membrane association of the PS (phosphatidylserine)-binding probe FITC-Annexin V in comparison with control cells was observed. Treatment of BCRP -overexpressing cells with the inhibitor Tryprostatin A decreased FITC-Annexin V binding almost to the control level. This suggests an enhanced exposure of PS in BCRP -overexpressing cells, which is dependent on functional BCRP. A role of BCRP in the transverse distribution of lipids in the plasma membrane is supported by the increased outward transport of the lipid analogue C6- N -(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-PS in BCRP -overexpressing EPG85-257 cells and MCF-7 human breast cancer cells. As shown for BCRP -overexpressing EPG85-257 cells, enhanced outward redistribution of the lipid analogue is inhibited by Tryprostatin A as well as by reduction of BCRP expression on transfection with an anti- BCRP -ribozyme. We also observed an enhanced outward transport of C6- N -(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-phosphatidylcholine in BCRP -overexpressing EPG85-257 cells, suggesting that the influence of BCRP on transverse lipid organization is not highly specific.
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PMID:Enhanced exposure of phosphatidylserine in human gastric carcinoma cells overexpressing the half-size ABC transporter BCRP (ABCG2). 1294 67

Recent studies in HER-2/neu-targeted immunotherapy demonstrated that polymorphonuclear neutrophils (PMN) mediated Ab-dependent cellular cytotoxicity against HER-2/neu-positive breast cancer cell lines. However, the mechanism of cell death remained unclear. We used several assays to analyze the induction of apoptosis in the breast cancer cell line SK-BR-3 via PMN-dependent Ab-dependent cellular cytotoxicity. In the presence of the HER-2/neu Ab 520C9 and PMN from healthy donors, apoptosis occurred as detected by annexin V binding and disappearance of euploid SK-BR-3 nuclei, which can be differentiated from PMN nuclei by their increased DNA contents. Apoptosis induction was observed with E:T cell ratios as low as 10:1. Laser scanning fluorescence microscopy of TUNEL tumor cells or staining for cleaved cytokeratin-18 further confirmed apoptosis of the SK-BR-3 breast cancer cells. Killing via 520C9 was dependent on the interaction with FcR on PMN, because 1) F(ab')(2) fragments of 520C9 mediated no cytotoxicity, 2) target cell death was influenced by a biallelic polymorphism of FcgammaRIIa on the effector cells, and 3) a bispecific Ab against HER-2/neu and the IgA receptor (FcalphaRI) expressed on effector cells significantly induced apoptosis. Thus, PMN induce Ab-dependent apoptosis against human breast cancer cells targeted with HER-2/neu-directed mAbs or FcR directed bispecific Abs.
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PMID:Polymorphonuclear granulocytes induce antibody-dependent apoptosis in human breast cancer cells. 1460 11

Tocotrienols, which are Vitamin E isoforms, are known to inhibit the growth of human breast cancer cells due partly to apoptosis. However, the characterization of tocotrienol-induced apoptosis is incomplete, particularly what happens during the initiation phase that precedes execution of the cells. The objective of this study was to clarify the apoptotic effects of tocotrienols, with especial emphasis in determining if the mitochondria-mediated death pathway is activated when human breast cancer cells are incubated with a specific tocotrienol isomer. During incubation with gamma-tocotrienol, MDA-MB-231 human breast cancer cells showed membrane blebbing, and apoptotic bodies were present. Upon 4',6-diamidino-2-phenylindole staining of the cells, chromatin condensation and fragmentation were observed. Additionally, the annexin V-binding assay detected the translocation of membrane phospholipid during earlier analysis of the cells. Taken together, these results further establish that gamma-tocotrienol can induce apoptosis in human breast cancer cells. To help elucidate how gamma-tocotrienol induced the apoptosis, some important parameters related to the mitochondria-mediated death pathway were examined next. In gamma-tocotrienol-treated cells, the mitochondria were disrupted. Collapse of the mitochondrial membrane potential was detected, and cytochrome c was released later from mitochondria. However, expression of Bax and Bcl-2 (mRNA and protein) did not change. Furthermore, poly-(ADP-ribose)-polymerase cleavage was not detected, suggesting that caspases were not involved in the gamma-tocotrienol-induced apoptosis. These results imply that cytochrome c is not the critical protein released from mitochondria that triggers gamma-tocotrienol-induced apoptosis in MDA-MB-231 cells.
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PMID:Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells. 1469 44

Recent evidence suggests a role for aberrant ceramide levels in the pathogenesis of cancer and chemoresistance and indicates that manipulation of tumor ceramide levels may be a useful strategy in the fight against breast cancer. This study demonstrates that alterations in the degree and position of unsaturation of bonds in the sphingoid backbone of d-erythro-N-octanoyl-sphingosine (Cer) affect the antiproliferative ability of ceramide analogs in breast cancer cells. The most potent analog of Cer we tested is (2S,3R)-(4E,6E)-2-octanoylamidooctadecadiene-1,3-diol (4,6-diene-Cer), which contains an additional trans double bond at C(6)-C(7) of the sphingoid backbone. 4,6-Diene-Cer exhibited higher potency than Cer in tumor necrosis factor (TNF)-alpha-resistant (IC(50) of 11.3 versus 32.9 microM) and TNF-alpha-sensitive (IC(50) of 13.7 versus 37.7 microM) MCF-7 cells. 4,6-Diene-Cer was also more potent than Cer in inducing cell death in MDA-MB-231 and NCI/ADR-RES breast cancer cell lines (IC(50) of 3.7 versus 11.3 microM, and 24.1 versus 86.9 microM, respectively). 4,6-Diene-Cer caused a prolonged elevation of intracellular ceramide levels in MCF-7 cells, which may contribute to its enhanced cytotoxicity. Furthermore, treatment of MCF-7 cells with Cer or 4,6-diene-Cer resulted in induction of apoptosis by 8 h via the mitochondrial pathway, as demonstrated by release of cytochrome c, loss of membrane asymmetry (measured by Annexin V staining), and a decrease in the mitochondrial membrane potential. Importantly, both Cer and 4,6-diene-Cer displayed selectivity toward transformed breast cells over nontransformed breast epithelial cells. These data suggest that these and other novel ceramide analogs represent potential therapeutic agents in breast cancer treatment.
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PMID:Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. 1474 41

Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor that mediates interferon and other cytokine effects and appears to have antitumor activity in vitro and in vivo in cancer cells. We have constructed a recombinant adenoviral vector (Ad-IRF-1) that infects mammary cells with high efficiency and results in high levels of functional IRF-1 protein in transfected cells. Overexpression of IRF-1 in two mouse breast cancer cell lines, C3-L5 and TS/A, resulted in apoptosis in these cell lines as assessed by Annexin V staining. The involvement of caspases was confirmed by significant inhibition of apoptosis by a caspase inhibitor, and by demonstration of caspase-3 activity, cleavage of caspase-3, and PARP cleavage. Interestingly, the growth of nonmalignant breast cell lines C127I and NMuMG did not appear to be inhibited by IRF-1 overexpression. Suppression of growth for breast cancer cell lines in vivo was demonstrated by both preinfection of breast cancer cells ex vivo and by intratumoral injection of Ad-IRF-1 into established tumors in their natural hosts. The mechanism of apoptosis may involve the transcriptional upregulation of bak, caspase-8, and caspase-7 expression. These data support the antitumor potential of IRF-1 and the use of agents that increase IRF-1 in breast cancer.
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PMID:IRF-1 expression induces apoptosis and inhibits tumor growth in mouse mammary cancer cells in vitro and in vivo. 1476 41

Hormone replacement therapy is contraindicated in women with breast cancer. Extracts from the rhizomes of Cimicifuga racemosa, have gained acceptance as a natural alternative for the treatment of menopausal symptoms. In the present study we investigated the antiproliferative activity of C. racemosa extracts (isopropanolic and ethanolic) on the estrogen receptor positive MCF-7 and estrogen receptor negative MDA-MB231 breast cancer cells by WST-1 assay. Down regulation of the proliferative activity and cell killing by isopropanolic and ethanolic extracts occurred in a clear dose-dependent response with a 50% growth inhibitory concentration of 54.1 +/- 11.4 and 80.6 +/- 17.7 micro g/ml in MCF-7 cells and of 29.5 +/- 3.0 and 58.6 +/- 12.6 microg/ml in MDA-MB231 cells, respectively. Further, the mode of cell death was identified as apoptosis by microscopic inspection and confirmed by light scatter characteristics and by detection of Annexin V adherence to phosphatidylserine by flow cytometry. In addition, the involvement of activated caspases was supported by the cleavage of cytokeratin 18 detected with M30 antibody. Increases in the level of M30-antigen of about 4-fold and 2-fold over untreated controls were observed in C. racemosa -treated MCF-7 and MDA-MB231 cells. These results indicate that C. racemosa extract exerts no proliferative activity, but kills the estrogen receptor positive MCF-7 as well as estrogen receptor negative MDA-MB231 cells by activation of caspases and induction of apoptosis.
Breast Cancer Res Treat 2004 Mar
PMID:Cimicifuga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell lines by induction of apoptosis. 1499 45

Incorporation of bromodeoxyuridine (BrdU) during DNA replication is frequently used for cell cycle analysis. The flow cytometric BrdU/Hoechst quenching technique is conducive to high-resolution assessment of cell cycle kinetics, but requires continuous BrdU treatment, which may have cytostatic or cytotoxic effects. Here, we have examined the impact of BrdU on the proliferation of BT474 and SK-BR-3 breast cancer cell lines and compared the observed effects with cell proliferation of RT4 and J82 bladder carcinoma cells, previously described to be sensitive and insensitive to BrdU, respectively. Both uni- and bi-parametric DNA measurements were performed to identify BrdU-induced alterations in the S-phase fraction and in cell cycle progression. An annexinV/propidium iodide (PI) assay was used to identify potential induction of apoptosis by BrdU. Proliferative activity in BT474, SK-BR-3, and RT4 cultures was reduced in different cell cycle phases due to continuous treatment with 60, 5.0, and 3.5 micro m BrdU. This effect, which was not found in J82 cultures, was dependent on exposure time (96 versus 48 h) and was also dose-dependent for RT4 and SK-BR-3. BrdU application does not induce apoptosis or necrosis as revealed with the annexin V/PI assay. We concluded that continuous BrdU treatment did not affect cell viability, but essentially alters cell cycle progression in three out of four cell lines tested. Cell-type specific validation of the feasibility of the powerful BrdU/Hoechst quenching technique is required and recommended.
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PMID:Exposure to continuous bromodeoxyuridine (BrdU) differentially affects cell cycle progression of human breast and bladder cancer cell lines. 1503 May 53


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