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)

The phosphatidylethanolamine (PE)-binding proteins (PEBPs) are an evolutionarily conserved family of proteins with pivotal biological functions. Here we describe the cloning and functional characterization of a novel family member, human phosphatidylethanolamine-binding protein 4 (hPEBP4). hPEBP4 is expressed in most human tissues and highly expressed in tumor cells. Its expression in tumor cells is further enhanced upon tumor necrosis factor (TNF) alpha treatment, whereas hPEBP4 normally co-localizes with lysosomes, TNFalpha stimulation triggers its transfer to the cell membrane, where it binds to Raf-1 and MEK1. L929 cells overexpressing hPEBP4 are resistant to both TNFalpha-induced ERK1/2, MEK1, and JNK activation and TNFalpha-mediated apoptosis. Co-precipitation and in vitro protein binding assay demonstrated that hPEBP4 interacts with Raf-1 and MEK1. A truncated form of hPEBP4, lacking the PE-binding domain, maintains lysosomal co-localization but has no effect on cellular responses to TNFalpha. Given that MCF-7 breast cancer cells expressed hPEBP4 at a high level, small interfering RNA was used to silence the expression of hPEBP4. We demonstrated that down-regulation of hPEBP4 expression sensitizes MCF-7 breast cancer cells to TNFalpha-induced apoptosis. hPEBP4 appears to promote cellular resistance to TNF-induced apoptosis by inhibiting activation of the Raf-1/MEK/ERK pathway, JNK, and PE externalization, and the conserved region of PE-binding domain appears to play a vital role in this biological activity of hPEBP4.
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PMID:A novel human phosphatidylethanolamine-binding protein resists tumor necrosis factor alpha-induced apoptosis by inhibiting mitogen-activated protein kinase pathway activation and phosphatidylethanolamine externalization. 3297 30

We previously blocked the heat shock transcription factor 1 function with a dominant-negative mutant (mHSF1) in breast cancer cell line Bcap37, and found that mHSF1 sensitizes Bcap37 cells to hyperthermia by promoting the apoptotic process. Here we studied the mechanism of this abolishing process and how thermotolerance develops in Bcap37 cells. The results indicated that mHSF1 abolished acquired or intrinsic thermotolerance in Bcap37 cells by enhancing JNK and caspase-3 pathways, two stress-induced apoptotic pathways, after hyperthermia, and interference with either one of them attenuated hyperthermia-induced apoptosis. Furthermore, epistasis assay of these two pathways suggested that JNK was upstream of the caspase-3 pathway. Conversely, other hyperthermia-induced kinases implicated in cell survival and death, Akt, ERK or p38, did not influence the effect of mHSF1, indicating that these kinases were not implicated in this abolishing process. In addition, we found that the development of acquired thermotolerance of Bcap37 cells was associated with the suppression of JNK activation after mild preheat treatment and was not reduced by Akt, ERK or p38 inhibition. In contrast, the intrinsic thermotolerance of Bcap37 cells was due to the intrinsic high levels of Akt and ERK activities since Akt or ERK inhibition resulted in increased thermosensitivity of Bcap37 cells. Our results suggest that mHSF1 plays a valuable role in the thermotolerance abolishment of Bcap37 cells, which likely contributes to tumor therapy in combination with hyperthermia.
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PMID:HSF1 blockade-induced tumor thermotolerance abolishment is mediated by JNK-dependent caspase-3 activation. 1535 68

1alpha,25-Dihydroxyvitamin D3 [1alpha,25(OH)2D3], the hormonally active form of vitamin D3, has been shown to be a potent negative growth regulator of breast cancer cells both in vitro and in vivo. 1alpha,25(OH)2D3 acts through two different mechanisms. In addition to regulating gene transcription via its specific intracellular receptor (vitamin D receptor, VDR), 1alpha,25(OH)2D3 induces rapid, non-transcriptional responses involving activation of transmembrane signal transduction pathways, like growth factors and peptide hormones. The mechanisms that mediate the antiproliferative effects of 1alpha,25(OH)2D3 in breast cancer cells are not fully understood. Particularly, there is no information about the early non-genomic signal transduction effectors modulated by the hormone. The present study shows that 1alpha,25(OH)2D3 rapidly inhibits serum induced activation of ERK-1 and ERK-2 MAP kinases. The tyrosine kinase Src is involved in the pathway leading to activation of ERK 1/2 by serum. Furthermore, 1alpha,25(OH)2D3 increases the tyrosine-phosphorylated state of Src and inhibits its kinase activity, while induces the association of the VDR with Src, either in the presence or absence of serum. In parallel, the hormone rapidly increases the amounts of VDR associated to plasma membranes (PM). Pretreatment with the tyrosine phosphatase inhibitors orthovanadate or bpV (phen) prevented mitogen-activated protein kinase (MAPK) inhibition by 1alpha,25(OH)2D3. These data altogether suggest that 1alpha,25(OH)2D3 inhibits the MAPK cascade by inactivating Src tyrosine kinase through a mechanism mediated by the VDR and tyrosine phosphatases.
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PMID:Inhibition of serum-stimulated mitogen activated protein kinase by 1alpha,25(OH)2-vitamin D3 in MCF-7 breast cancer cells. 1536 64

Transforming growth factor (TGF)-beta has been reported to exert growth inhibitory activity in normal epithelial cells whereas it induces cell proliferation and invasive phenotypes in advanced carcinomas. Our previous study showed that MCF10A, a spontaneously immortalized "normal" breast epithelial cell line, is resistant to TGF-beta-induced growth inhibition, suggesting that conversion of TGF-beta growth inhibitory signaling into an oncogenic pathway may occur at the early stage of tumor development/progression. To address this issue, we investigated the TGF-beta signaling pathway and its role in phenotypic transformation of MCF10A cells. TGF-beta treatment induced changes in the MCF10A cell morphology from cuboidal to an elongated spindle-like shape, accompanied with down-regulation of epithelial cell marker E-cadherin. TGF-beta treatment was sufficient to induce migrative and invasive phenotypes in these cells, an important phenotypic conversion during tumor progression. We also showed that TGF-beta treatment rapidly activated ERK-1/2 and p38 MAPK leading to upregulation of matrix metalloproteinase (MMP)-2 and MMP-9. Using chemical inhibitors and dominant negative mutants of MAPKs, we provide evidence that while both p38 MAPK and ERKs are required for TGF-beta-induced MCF10A cell migration and invasion, TGF-beta-induced MMP-2 and MMP-9 expression depends on p38 MAPK signaling, but is independent of ERK activity. This study demonstrates the roles of TGF-beta signaling pathways for induction of oncogenic signaling in preneoplastic human breast epithelial cells and will deepen our understanding of TGF-beta signaling in the progress of breast cancer.
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PMID:TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. 1549 28

We evaluated the signaling pathways involved in regulating vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, in response to natural and synthetic progestins in breast cancer cells. Inhibition of the phosphoinositide-3'-kinase (PI3-kinase) signaling pathway or the specificity protein-1 (SP-1) transcription factor abolished both progesterone- and medroxyprogesterone acetate (MPA)-induced VEGF secretion from BT-474 and T47-DCO)cells. Inhibitors of the MAPK kinase 1/2/MAPK and N-terminal jun kinase/MAPK signaling pathways blocked both progesterone- and MPA-induced VEGF secretion in BT-474 cells. However, these inhibitors blocked only progesterone-, but not MPA-induced VEGF secretion in T47-DCO cells. Inhibitors of PI3-kinase or SP-1 blocked both progesterone- and MPA-induced increases in VEGF mRNA levels in T47-DCO cells. The proximal SP-1 sites within the VEGF promoter were critical for progestin-dependent induction of VEGF. In contrast, MAPK inhibitors did not block the progesterone- or MPA-induced increases in VEGF mRNA in T47-DCO cells, suggesting that MAPK inhibitors decreased progesterone-induced VEGF secretion in T47-DCO cells by blocking posttranscriptional mechanisms. The MAPK kinase/ERK/MAPK-independent induction of VEGF mediated by MPA was associated with the PRB [progesterone receptor (PR) B] isoform of the PR in T47-DCO cells. None of the inhibitors tested reduced basal PR levels or abrogated PR-dependent gene expression from a reporter plasmid, indicating that loss of PR function cannot explain any of the observed effects. Because the PI3-kinase signaling pathway and SP-1 transcription factor play critical roles in progestin-dependent VEGF induction, these may be useful targets for developing antiangiogenic therapies to prevent progression of progestin-dependent human breast cancers.
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PMID:Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced vascular endothelial growth factor levels in human breast cancer cells. 1552 72

Human WWOX gene encodes a proapoptotic WW domain-containing oxidoreductase WOX1 (also named WWOX, FOR2 or WWOXv1). Apoptotic and stress stimuli activate WOX1 via Tyr33 phosphorylation and nuclear translocation. WOX1 possesses a tetrad NSYK motif in the C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, which may bind estrogen and androgen. Here, we determined that 17beta-estradiol (E(2)) activated WOX1, p53 and ERK in COS7 fibroblasts, primary lung epithelial cells, and androgen receptor (AR)-negative prostate DU145 cells, but not in estrogen receptor (ER)-positive breast MCF7 cells. Androgen also activated WOX1 in the AR-negative DU145 cells. These observations suggest that sex hormone-mediated Tyr33 phosphorylation and nuclear translocation of WOX1 is independent of ER and AR. Stress stimuli increase physical binding of p53 with WOX1 in vivo. We determined here that E(2) increased the formation of p53/WOX1 complex and their nuclear translocation in COS7 cells; however, nuclear translocation of this complex could not occur in MCF7 cells. By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2). In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis. These Tyr33-phosphorylated proteins are mostly located in the mitochondria without translocating to the nuclei, which is comparable to those findings in cultured breast cancer cells. Together, sex steroid hormone-induced activation of WOX1 and WOX2 is independent of ER and AR, and this activation positively correlates with cancerous progression of prostate and breast to a premetastatic state.
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PMID:17beta-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo. 1558 Mar 10

Epidermal growth factor receptor (EGFR) is activated by autocrine growth factors in many types of tumours, including breast tumours. This receptor has been linked to a poor prognosis in breast cancer and may promote proliferation, migration, invasion, and cell survival as well as inhibition of apoptosis. Human breast ductal carcinoma MCF7 cells were transfected using FuGENE 6 with 1 microg of pcDNA3-EGFR containing the full-length human EGFR promoter or 1 microg of the vectors alone (pcDNA3). The transfected cells were transferred into a 25-cm2 flask containing growth medium and G418. Confluent cultures were lysed, total protein levels measured and electrophoresed. The electrophoresed samples were transferred to nitrocellulose and incubated overnight at 4 degrees C with either anti-EGFR or anti-phospho-ERK and immunoreactive bands were visualized using HRP-linked secondary antibody. We created a model system of EGFR overexpression in MCF7 clones with stably transfected pcDNA3/EGFR plasmid. These cells have been shown to promote substantial phosphorylation of both ERK1 and ERK2. The high level of EGFR and ERK1/2 phosphorylation was not seen in the pcDNA3 vector control cells or in non-transfected cells. In this article we describe successful transient transfection experiments on MCF7 cells using the FuGENE 6 Transfection Reagent. The overexpression of EGFR could be a mediated stress response and a survival signal that involves ERK1 and ERK2 phosphorylation.
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PMID:Transient transfection of epidermal growth factor receptor gene into MCF7 breast ductal carcinoma cell line. 1558 89

This study first investigates the anticancer effect of asiatic acid in two human breast cancer cell lines, MCF-7 and MDA-MB-231. Asiatic acid exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels and reduced amounts of cyclinB1, cyclinA, Cdc2, and Cdc25C in a p53-independent manner. Asiatic acid also reduced Cdc2 function by increasing the association of p21/WAF1/Cdc2 complex and the level of inactivated phospho-Cdc2 and phospho-Cdc25C. Asiatic acid treatment triggered the mitochondrial apoptotic pathway indicated by changing Bax/Bcl-2 ratios, cytochrome c release, and caspase-9 activation, but it did not act on Fas/Fas ligand pathways and the activation of caspase-8. We also found that mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2), and p38, but not c-Jun NH2-terminal kinase (JNK), are critical mediators in asiatic acid-induced cell growth inhibition. U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], specific inhibitors of mitogen-activated protein kinase kinase and p38 kinase activities, significantly decreased or delayed apoptosis. Asiatic acid was likely to confine the breast cancer cells in the S-G2/M phase mainly through the p38 pathway, because both SB203580 and p38 small interfering RNA (siRNA) inhibition significantly attenuated the accumulation of inactive phospho-Cdc2 and phospho-Cdc25C proteins and the cell numbers of S-G2/M phase. Moreover, U0126 and ERK siRNA inhibition completely suppressed asiatic acid-induced Bcl-2 phosphorylation and Bax up-regulation, and caspase-9 activation. Together, these results imply a critical role for ERK1/2 and p38 but not JNK, p53, and Fas/Fas ligand in asiatic acid-induced S-G2/M arrest and apoptosis of human breast cancer cells.
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PMID:Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells. 1562 23

We have shown that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces in vitro invasiveness and metastatic capacity of MDA-MB-435 breast cancer cells. These experiments investigated the mechanisms mediating the anti-invasive properties of DFMO. DFMO did not affect phosphorylation of FAK or Akt, but increased ERK phosphorylation by approximately threefold. To test the biologic significance of this finding, we tested the effect of the MEK inhibitor PD98059 on in vitro invasiveness of MDA-MB-435 breast cancer cells, both in the absence and in the presence of the proinvasive peptide hepatocyte growth factor (HGF) as a chemoattractant. We observed that PD98059 treatment reversed the anti-invasive effect of DFMO under both experimental conditions. Next, we tested the influence of DFMO on the production of the prometastatic peptide osteopontin (OPN) and the anti-metastatic protein thrombospondin-1 (TSP-1). DFMO treatment, while not affecting OPN production, markedly increased the TSP-1 level in the conditioned media. This effect was abolished by putrescine administration, thus indicating the specificity of the DFMO action through the polyamine pathway. PD98059 completely blocked the stimulatory effect of DFMO on TSP-1 production, which supports a mediatory role for activation of the MAPK pathway in the upregulation of this anti-metastatic peptide by DFMO. In summary, our results show that the increase in ERK phosphorylation induced by DFMO plays a critical role in the anti-invasive action of the drug and in its ability to upregulate TSP-1 production.
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PMID:Cellular mechanisms mediating the anti-invasive properties of the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) in human breast cancer cells. 1567 71

Hypoxia-inducible factor (HIF) is critical in the modulation of tumour angiogenesis in response to hypoxia. In the present study, the mechanisms underlying basic fibroblast growth factor (bFGF)-induced activation of HIF-1 and the subsequent release of vascular endothelial growth factor (VEGF) in a human breast cancer cell line (T47D) under normoxic conditions were explored. The data show that HIF-1alpha expression is induced by bFGF in a dose- and time-dependent fashion, while increased HIF-1alpha protein expression and transactivity of HIF-1 are due to the phosphorylation of Akt by bFGF, as indicated by application of the phosphatidylinositol 3-kinase (PI-3K) inhibitor LY294002. The data also show that the MEK1 (mitogen-activated protein kinase kinase-1)/ERK (extracellular signal-regulated kinase) pathway is only involved in bFGF-induced transactivity of HIF-1, but not HIF-1alpha expression, indicating roles for both the PI-3K/Akt and the MEK1/ERK pathways in bFGF activity. In addition, the translation inhibitor cycloheximide confirmed that bFGF-induced HIF-1alpha protein expression was due to de novo protein synthesis. In contrast, p38 was not required for the expression of HIF-1alpha or HIF-1 transactivity, although significant phosphorylation of p38 was observed after bFGF treatment. Treatment of the cells with bFGF increased the amount of VEGF release, and this could be suppressed by either PD98059 or LY294002, suggesting the presence of a HIF-1alpha-dependent pathway for bFGF-induced VEGF production. In conclusion, the PI-3K/Akt and MEK1/ERK pathways, in a potentially independent and co-operative fashion, can modulate HIF-1 activation by bFGF. Further studies will pinpoint whether HIF-1 is the transcriptional factor responsible for the increased VEGF production following bFGF treatment of breast tumour cells.
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PMID:In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. 1571 61


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