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)

Glucose-regulated proteins (GRPs) are induced in cells by a variety of stress conditions such as treatment with 2-deoxyglucose, glucosamine, or the calcium ionophore A23187. We found that resistance to topoisomerase II (topo II) inhibitors, VP-16 and adriamycin, was induced by these treatments in human colon cancer HT-29 cells. Similar VP-16 resistance occurred in human ovarian cancer A2780 and breast cancer MCF-7 cells. The VP-16 resistance was reversible, since the sensitivity of the cells to VP-16 recovered within 24 h after the stresses were removed. Western blotting analysis showed that under these stress conditions the cellular contents of topo II alpha were decreased. The decreased expression of topo II was reversed to control levels within 24 h following removal of the stresses. The decrease in topo II levels under the stress conditions correlated well with the induction of GRP78 and 94. The close correlation between topo II and GRPs suggests that topo II is a protein sensitive to the glucose-regulated stresses. Since hypoxia and nutrient deprivation, which are also GRP-inducing conditions, could occur naturally in the solid tumors, the stress-associated cellular resistance through decrease in topo II levels may be a mechanism of the natural resistance of the solid tumors to topo II-directed chemotherapy.
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PMID:Glucose-regulated stresses confer resistance to VP-16 in human cancer cells through a decreased expression of DNA topoisomerase II. 870 75

The stress-inducible glucose regulated proteins (GRPs), a class of calcium-binding molecular chaperones localized in the endoplasmic reticulum, have been implicated in the development of tumorigenicity, drug resistance, and cytotoxic immunology. This study investigates the expression pattern of GRP94 and GRP78 in a panel of breast carcinoma cell lines, as compared to two independently derived normal human breast epithelial cell lines. Here we report that a 3- to 5-fold increase in the basal level of the GRP94 protein was observed in all five breast carcinoma cell lines examined. The increase was independent of either the p53 or estrogen receptor status of the breast carcinomas. In carcinoma cells deprived of glucose, mimicking the conditions in poorly vascularized solid tumors, up to 9-fold induction of GRP94 was observed relative to the basal level expressed in a normal breast epithelial cell line. Interestingly, while the majority of the breast cancer cell lines can respond to tunicamycin- and thapsigargin-induced stress by increasing the steady state levels of grp94 and grp78 transcripts, the induction at the GRP protein level is variable and does not always correspond with the transcript level. Further, we discovered that one of the human breast carcinoma cell lines, MCF-7, has specifically lost its ability to respond to tunicamycin stress.
Breast Cancer Res Treat 1999 Mar
PMID:De-regulation of GRP stress protein expression in human breast cancer cell lines. 1042 4

The 78 kDa glucose-regulated stress protein GRP78 is induced by physiological stress conditions such as hypoxia, low pH, and glucose deprivation which often exist in the microenvironments of solid tumors. Activation of this stress pathway occurs in response to several pro-apoptotic stimuli. In vitro studies have demonstrated a correlation between induced expression of GRP78 and resistance to apoptotic death induced by topoisomerase II-directed drugs. We were interested in characterizing this protein in human breast lesions for potential implications in chemotherapeutic intervention. Surgical specimens of human breast lesions and paired normal tissues from the same patients were flash frozen for these studies. Total RNA and/or protein were extracted from these tissues and used in northern and/or western blot analyses, respectively, to quantify the relative expression of GRP78. Northern blot analysis indicated that 0/5 benign breast lesions, 3/5 estrogen receptor positive (ER+) breast tumors, and 6/9 estrogen receptor negative (ER-) breast tumors exhibited overexpression of GRP78 mRNA compared to paired normal tissues, with fold overexpressions ranging from 1.8 to 20. Western blot analyses correlated with these findings since 0/5 benign breast lesions, 4/6 ER+ breast tumors, and 3/3 ER- breast tumors overexpressed GRP78 protein with fold overexpressions ranging from 1.8 to 19. Immunohistochemical analysis of these tissues demonstrated that the expression of GRP78 was heterogeneous among the cells comprising different normal and malignant glands, but confirmed the overexpression of GRP78 in most of the more aggressive ER- tumors. These results suggest that some breast tumors exhibit adverse microenvironment conditions that induce the overexpression of specific stress genes that may play a role in resistance to apoptosis and decreased chemotherapeutic efficacy.
Breast Cancer Res Treat 2000 Jan
PMID:Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. 1075 76

Anticancer drugs often show complex mechanisms of action, including effects on multiple cellular targets. Detailed understanding of these intricate effects is important for the understanding of cytotoxicity. In this study, we examined apoptosis induction by ellipticines, a class of cytotoxic plant alkaloids known to inhibit topoisomerase II. The potent ellipticine derivative 6-propanamine ellipticine (6-PA-ELL) induced rapid apoptosis in MDA-MB-231 breast cancer cells, preceded by a conformational change in Bak and cytochrome c release. Experiments using knock-out mouse embryo fibroblasts established that Bak was of particular importance for cytotoxicity. 6-PA-ELL increased the expression of the endoplasmic reticulum chaperones GRP78/BiP and GRP94, suggesting induction of endoplasmic reticulum stress. Induction of GRP78 expression was dependent on the endoplasmic reticulum stress response element (ERSE) of the GRP78 promoter. Examination of different ellipticine derivatives revealed a correlation between pro-apoptotic activity and the ability to induce GRP78 expression. Furthermore, 6-PA-ELL was found to induce splicing of the mRNA encoding the XBP1 transcription factor, characteristic of endoplasmic reticulum stress, and to induce activation of the endoplasmic reticulum-specific caspase-12 in mouse colon cancer cells. We finally demonstrate that 6-PA-ELL induces apoptotic signaling also in enucleated cells, consistent with the existence of a cytoplasmic target for this compound. Our data suggest that induction of endoplasmic reticulum stress may contribute to the cytotoxicity of ellipticines.
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PMID:Induction of endoplasmic reticulum stress by ellipticine plant alkaloids. 1507 93

Therapeutic targeting of the tumor vasculature that destroys preexisting blood vessels of the tumor and antiangiogenesis therapy capitalize on the requirement of tumor cells on an intact vascular supply for oxygen and nutrients for growth, expansion and metastasis to the distal organs. Whereas these classes of agents show promise in delaying tumor progression, they also create glucose and oxygen deprivation conditions within the tumor that could trigger unintended prosurvival responses. The glucose-regulated protein GRP78, a major endoplasmic reticulum chaperone, is inducible by severe glucose depletion, anoxia, and acidosis. Here we report that in a xenograft model of human breast cancer, treatment with the vascular targeting agent, combretastatin A4P, or the antiangiogenic agent, contortrostatin, promotes transcriptional activation of the Grp78 promoter and elevation of GRP78 protein in surviving tumor cells. We further show that GRP78 is overexpressed in a panel of human breast cancer cells that has developed resistance to a variety of drug treatment regimens. Suppression of GRP78 through the use of lentiviral vector expressing small interfering RNA sensitizes human breast cancer cells to etoposide-mediated cell death. Our studies imply that antivascular and antiangiogenesis therapy that results in severe glucose and oxygen deprivation will induce GRP78 expression that could lead to drug resistance.
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PMID:Vascular targeting and antiangiogenesis agents induce drug resistance effector GRP78 within the tumor microenvironment. 1599 54

The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. In vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to "time to recurrence" (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; P = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies.
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PMID:GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. 1691 56

The identification of drug-responsive biomarkers in complex protein mixtures is an important goal of quantitative proteomics. Here, we describe a novel approach for identifying such drug-induced protein alterations, which combines 2-nitrobenzenesulfenyl chloride (NBS) tryptophan labeling with two-dimensional gel electrophoresis (2DE)/mass spectrometry (MS). Lysates from drug-treated and control samples are labeled with light or heavy NBS moiety and separated on a common 2DE gel, and protein alterations are identified by MS through the differential intensity of paired NBS peptide peaks. Using NBS/2DE/MS, we profiled the proteomic alterations induced by tamoxifen (TAM) in the estrogen receptor (ER) positive MCF-7 breast cancer cell line. Of 88 protein spots that significantly changed upon TAM treatment, 44 spots representing 23 distinct protein species were successfully identified with NBS-paired peptides. Of these 23 TAM-altered proteins, 16 (70%) have not been previously associated with TAM or ER activity. We found the NBS labeling procedure to be both technically and biologically reproducible, and the NBS/2DE/MS alterations exhibited good concordance with conventional 2DE differential protein quantitation, with discrepancies largely due to the comigration of distinct proteins in the regular 2DE gels. To validate the NBS/2DE/MS results, we used immunoblotting to confirm GRP78, CK19, and PA2G4 as bona fide TAM-regulated proteins. Furthermore, we demonstrate that PA2G4 expression can serve as a novel prognostic factor for disease-free survival in two independent breast cancer patient cohorts. To our knowledge, this is the first report describing the proteomic changes in breast cancer cells induced by TAM, the most commonly used selective estrogen receptor modulator (SERM). Our results indicate that NBS/2DE/MS may represent a more reliable approach for cellular protein quantitation than conventional 2DE approaches.
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PMID:Quantitative profiling of drug-associated proteomic alterations by combined 2-nitrobenzenesulfenyl chloride (NBS) isotope labeling and 2DE/MS identification. 1694 31

The recent development of hormonal therapy that blocks estrogen synthesis represents a major advance in the treatment of estrogen receptor-positive breast cancer. However, cancer cells often acquire adaptations resulting in resistance. A recent report reveals that estrogen starvation-induced apoptosis of breast cancer cells requires BIK, an apoptotic BH3-only protein located primarily at the endoplasmic reticulum (ER). Searching for novel partners that interact with BIK at the ER, we discovered that BIK selectively forms complex with the glucose-regulated protein GRP78/BiP, a major ER chaperone with prosurvival properties naturally induced in the tumor microenvironment. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For estrogen-dependent MCF-7/BUS breast cancer cells, overexpression of GRP78 inhibits estrogen starvation-induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by small interfering RNA (siRNA) sensitizes MCF-7/BUS cells to estrogen starvation-induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. Our results provide the first evidence that GRP78 confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK. These results further suggest that GRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP78 may enhance efficacy and reduce resistance.
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PMID:GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. 1744 86

The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity.
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PMID:Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. 1819 45

Baicalein was investigated for tumor cell-specific cytotoxicity, apoptosis-inducing activity and signal pathway against the MDA-MB-231 human breast cancer cell line. After the MDA-MB-231 cells had been treated with baicalein, trypan blue exclusion, propidium iodide (PI) assay and 4',6-diamidino-2-phenylindole (DAPI) were used to stain the dead cells and detect apoptosis, respectively. The effects of baicalein on the levels of reactive oxygen species (ROS), Ca2+ and mitochondrial membrane potential (deltapsim) on MDA-MB-231 cells were examined by flow cytometric assays. The ROS caused endoplasmic reticulum (ER) stress, confirmed by the increase of GADD153 and GRP78 in the examined cells. GADD153 and GRP78 increases were also confirmed by confocal laser microscopy examination and indicated that both proteins translocated to the nucleus. The effects of baicalein on the expression of apoptotic-regulated genes, such as Bcl-2 family and caspase, were detected by Western blotting. To further investigate the apoptotic pathway and the role of Ca2+ induced by baicalein, a caspase-3 inhibitor and Ca2+ chelator were used to block caspase-3 activity and Ca2+ in MDA-MB-231 cells. Baicalein induced apoptosis in a time-dependent effect through the inhibition of Bcl-2 expression, increased the levels of Bax, reduced the level of deltapsim, and promoted the cytochrome c release and caspase-3 activation. MDA-MB-231 cells were pretreated with BAPTA which reduced the levels of Ca2+, deltapsim and apoptosis. In conclusion, baicalein induced apoptosis via Ca2+ production, mitochondria-dependent and caspase-3 activation in MDA-MB-231 cells.
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PMID:The role of Ca2+ in baicalein-induced apoptosis in human breast MDA-MB-231 cancer cells through mitochondria- and caspase-3-dependent pathway. 1863 May 29


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