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)

MDA-MB-468 human breast cancer cells lack estrogen receptors, overexpress epidermal growth factor (EGF) receptors, and are growth inhibited by EGF. We show that treatment of MDA-MB-468 cells with EGF leads to inhibition of cell proliferation, fragmentation of DNA into nucleosomal oligomers, and the development of apoptotic morphology. This treatment is associated with increased expression of c-myc, c-fos, jun family members, and transforming growth factor beta 1 mRNA and with partial proteolytic cleavage of poly(ADP-ribose) polymerase and lamin B. The observation that EGF can mediate apoptosis in EGF receptor-overexpressing cells has important implications for clinical efforts directed at the EGF receptor.
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PMID:Epidermal growth factor-mediated apoptosis of MDA-MB-468 human breast cancer cells. 792 54

An inhibitor of poly(ADP-ribose) polymerase is 3-aminobenzamide (3AB), treatment by which normally results in the decreased levels of rejoining of DNA single strand breaks. We have studied the effect of 3AB in gamma-irradiation induced damage and the subsequent repair of DNA along with the corresponding changes in poly (ADP-ribose) polymerase activity in lymphocytes of patients with the cancer of breast and uterine cervix. The presence or absence of 3AB prior to gamma-irradiation did not influence the extent of DNA damage. On the other hand, single strand breaks rejoining in breast cancer cases was found to be slower as compared to that of cervical cancer cases and normal individuals. The relative ADP-ribosylation in the presence of 3AB was much lower in the breast cancer cases as compared to normal but there was no significant change in the cervical cancer cases. Overall the maximum relative ADP-ribosylation was slower in the presence of 3AB. This suggests that the lower activity of poly (ADP-ribose) polymerase in breast cancer cases might delay the first phase of single strand breaks (SSBs) rejoining.
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PMID:3-Aminobenzamide delays rejoining of DNA strand breaks in gamma-irradiated lymphocytes from patients with breast cancer and not cervical cancer. 793 83

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the M(r) 116,000 pADPRp polypeptide to an M(r) approximately 25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an M(r) approximately 85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the M(r) approximately 85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum(II), colcemid, 1-beta-D-arabinofuranosylcytosine, and methotrexate; to gamma-irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2'-deoxyuridine and in gamma-irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-L-lysine chloromethyl ketone, tosyl-L-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.
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PMID:Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. 835 26

The importance of a genetic polymorphism (A/B allele) of poly(ADP-ribose) polymerase (PARP) pseudogene on chromosome 13q34-qter, and PARP enzyme activities in the development of human breast cancer were evaluated in a cancer case-control study. A total of 309 Caucasian women (> or = 50 years old) were evaluated for the PARP genotype, 70 of whom had histologically confirmed breast cancer, 128 women with benign breast diseases as study controls, and 111 reference controls. Age was significantly associated with case-control status (p < 0.0001), but family history of breast cancer, age at menarche, age at first live birth and parity were not. The frequency of the PARP B allele was similar in breast cancer cases (0.14), study controls (0.13), and reference controls (0.15). In a subset of 14 breast cancer cases and 32 study controls, the mean PARP enzyme activities (induced by H2O2 or oligonucleotide) were observed to be lower in cancer cases; an age-adjusted odds ratio of 3.40 (95% confidence interval = 0.70-19.54) for the below-median oligonucleotide-induced PARP was suggestive of an association. In subjects with the AB or BB genotype, the mean H2O2-induced PARP enzyme activity was significantly higher (p = 0.02, adjusted for case-control status and age) compared with that in subjects with the AA genotype. These findings indicate that: (a) the genetic polymorphism of the PARP pseudogene on chromosome 13 is not associated with the development of breast cancer in our study population; (b) oligonucleotide-induced PARP activity may be useful for identifying postmenopausal women at increased risk for breast cancer; and (c) there is a possible functional link between the genotype of the PARP pseudogene and enzyme activation.
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PMID:Poly(ADP-ribose) polymerase in human breast cancer: a case-control analysis. 929 59

p27Kip1, a cyclin-dependent kinase inhibitor, is recognized as a negative regulator of the cell cycle. In this paper, we report that overexpression of p27Kip1 triggers apoptosis in several different human cancer cell lines. Using a recombinant adenoviral vector that expresses p27Kip1 (Adp27), we found that overexpression of p27Kip1 in MDA-MB-231 breast cancer cells induces apoptosis that was seen by a number of different techniques, including flow cytometry and in situ terminal deoxynucleotidyl transferase-mediated nick end labeling, flow cytometric assay for sub-G1 population, and 4',6-diamindino-2-phenylindole staining. Cleavage of poly(ADP-ribose) polymerase and degradation of cyclin B1, events that are known to be associated with apoptosis, were also observed following overexpression of p27Kip1. This is the first report indicating a role for p27Kip1 in induction of apoptosis.
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PMID:Promoting apoptosis: a novel activity associated with the cyclin-dependent kinase inhibitor p27. 940 46

Interleukin-4 (IL-4) is a pleiotropic cytokine produced by mast cells and T lymphocytes that promotes proliferation and immunoglobulin class-switching in B cells. IL-4 receptors (IL-4Rs) are also expressed by nonhematopoietic cells as well as some tumor cells. Unlike its mitogenic effect on B cells, IL-4 inhibits the growth of some cancer cells in vitro. In this study, we show that IL-4R is expressed by breast and ovarian cancer cell lines. Furthermore, anchorage-dependent and -independent growth of breast cancer cell lines MCF-7 and MDA-MB-231 is inhibited by IL-4 treatment, and this effect requires IL-4R. Interestingly, IL-4 only inhibited proliferating breast cancer cells and had no effect on basal, unstimulated growth. We therefore characterized the effect of IL-4 on breast cancer cell growth stimulated by either estradiol or insulin-like growth factor I (IGF-I). In both anchorage-dependent and -independent growth assays, IL-4 inhibited estradiol-stimulated growth. The antiestrogen effect of IL-4 was not due to IL-4 interference with the estrogen receptor, because IL-4 did not interfere with estrogen receptor-mediated reporter gene transactivation. In contrast, IL-4 had no effect on IGF-I-stimulated proliferation. Because IGF-I is known to inhibit programmed cell death, we examined apoptosis as a possible mechanism of IL-4 action. We established that IL-4 induced apoptosis in breast cancer cells by five independent criteria: (a) morphological indicators including pyknotic nuclei and cytoplasmic condensation; (b) DNA fragmentation; (c) the formation of DNA laddering; (d) the cleavage of poly(ADP-ribose) polymerase; and (e) the presence of cells with sub-G1 DNA content. IL-4 increased the percentage of apoptotic cells in MCF-7 and MDA-MB-231 cells 6.0- and 6.7-fold over that of the control, respectively. Finally, the addition of IGF-I reversed IL-4-induced apoptosis, suggesting that the mechanism of IL-4-induced growth inhibition in human breast cancer cells is the induction of programmed cell death.
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PMID:Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells. 975 35

A two-color flow cytometric technique was developed to analyze poly(ADP-ribose) polymerase (PADPRP) in different individuals as a function of different physiological or pathological conditions and to establish the basis for determining whether enzyme deficiency may predispose to degenerative or malignant disorders. Peripheral blood granulocytes were devoid of enzyme activity, whereas mononuclear cells had variable amounts. PADPRP was highest in B cells, intermediate in T cells, and lowest in monocytes. This pattern of enzyme distribution and relative enzyme content of different types of cells was remarkably constant in normal subjects. In a series of 66 normal donors there was no significant biological variation in enzyme content as a function of age, race, or sex. The mean PADPRP values in peripheral blood mononuclear cells from 81 random patient samples obtained from an ambulatory oncology clinic did not differ significantly from normal subjects. However, groups of patients with breast cancer, lymphocytic malignancies, and esophageal cancer were observed to have below normal levels for peripheral blood mononuclear cell PADPRP.
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PMID:Poly(adenosine diphosphoribose) polymerase in peripheral blood leukocytes from normal donors and patients with malignancies. 981 77

The ability of paclitaxel, one of the most active chemotherapeutic agents against breast cancer, to induce programmed cell death in hormone-independent MDA-MB-468 human breast cancer cells was assessed. Treatment of MDA-MB-468 cells led to growth inhibition, high-molecular-weight and oligonucleosomal DNA fragmentation, and apoptosis-associated morphological changes after either 3- or 24-h exposure to paclitaxel concentrations >/=10 nM. Additionally, cleavage products of poly(ADP-ribose) polymerase and lamin B1, two proteins that are cleaved early in the execution phase of programmed cell death, were detected. Quantitative studies indicated that exposure to paclitaxel for 24 h resulted in more DNA fragmentation than did 3-h exposure. Rapid induction of the early-response gene c-jun but not c-myc was associated with paclitaxel treatment. The ability of paclitaxel to induce high-molecular-weight DNA fragmentation and apoptosis-associated morphological changes in three other breast cancer cell lines was also established. These data suggest that paclitaxel, an agent known to stabilize microtubules and prevent cell division but not to act directly on DNA, induces programmed cell death in breast cancer cells.
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PMID:Paclitaxel induces programmed cell death in MDA-MB-468 human breast cancer cells. 981 40

Previous studies have demonstrated that topoisomerase I is cleaved late during apoptosis, but have not identified the proteases responsible or examined the functional consequences of this cleavage. Here, we have shown that treatment of purified topoisomerase I with caspase-3 resulted in cleavage at DDVD146 downward arrowY and EEED170 downward arrowG, whereas treatment with caspase-6 resulted in cleavage at PEDD123 downward arrowG and EEED170 downward arrowG. After treatment of Jurkat T lymphocytic leukemia cells with anti-Fas antibody or A549 lung cancer cells with topotecan, etoposide, or paclitaxel, the topoisomerase I fragment comigrated with the product that resulted from caspase-3 cleavage at DDVD146 downward arrowY. In contrast, two discrete topoisomerase I fragments that appeared to result from cleavage at DDVD146 downward arrowY and EEED170 downward arrowG were observed after treatment of MDA-MB-468 breast cancer cells with paclitaxel. Topoisomerase I cleavage did not occur in apoptotic MCF-7 cells, which lack caspase-3. Cell fractionation and band depletion studies with the topoisomerase I poison topotecan revealed that the topoisomerase I fragment remains in proximity to the chromatin and retains the ability to bind to and cleave DNA. These observations indicate that topoisomerase I is a substrate of caspase-3 and possibly caspase-6, but is cleaved at sequences that differ from those ordinarily preferred by these enzymes, thereby providing a potential explanation why topoisomerase I cleavage lags behind that of classical caspase substrates such as poly(ADP-ribose) polymerase and lamin B1.
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PMID:Caspase-mediated cleavage of DNA topoisomerase I at unconventional sites during apoptosis. 993 35

Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.
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PMID:Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. 997 25


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