UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of heat shock protein 70 kDa alters the susceptibility of tumor cells to chemotherapeutic agents. We conducted experiments to study the regulation of expression of heat shock proteins (HSPs) in heat shock-treated T47-D cells, a human breast cancer cell line that expresses estrogen receptors. Cells exposed to heat shock at 44 degreesC displayed increased expression of heat shock protein 72 kDa (HSP-72), glucose-regulated protein 78 kDa (GRP-78), and GRP-94 in a time-dependent manner, as shown by [35S]methionine incorporation and Western blotting experiments. The maximal rate of synthesis occurred between 2 and 4 h after heat shock. Removal of external Ca2+ inhibited the synthesis of the heat shock-induced GRP-78 but not of HSP-72 and GRP-94, whereas treatment of cells with BAPTA (a Ca2+ chelator) inhibited HSP-72 and GRP-78. Treatment with H89 (a protein kinase A inhibitor) blocked the heat shock-induced GRP-78 synthesis, whereas GF-109203X (a protein kinase C inhibitor) attenuated the heat shock-induced HSP-72 synthesis and completely blocked synthesis of GRP-78 but not of GRP-94. These results indicate that protein kinase C is involved in regulation of the heat shock-induced synthesis of HSP-72, whereas PKA and PKC are involved in the regulation of GRP-78 synthesis. Cells overexpressing HSP-72 and GRPs after heat shock displayed resistance against lethal temperature (47 degreesC for 50 min) -induced death, which was diminished after removal of external Ca2+ and treatment with GF-109203X. Heat shock increased intracellular free Ca2+ concentration ([Ca2+]i) in a temperature- and heating duration-dependent fashion, and the increase was inhibited in the absence of external [Ca2+]i and significantly reduced by pretreatment with H89 and GF-109203X. The results suggest that different pathways are involved in the induction of synthesis of HSP-72, GRP-78, and GRP-94 by heat shock. It is highly likely that only HSP-72 and GRP-78 are involved in the process of cytoprotection from the thermal injury.
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PMID:Cytoprotection and regulation of heat shock proteins induced by heat shock in human breast cancer T47-D cells: role of [Ca2+]i and protein kinases. 980 66

Heat shock alters the susceptibility of tumor cells to chemotherapeutic agents. Cultured breast cancer MCF-7 and MDA-MB-231 cells that express high levels of heat shock protein 70 and 27 kDa are resistant to treatment with certain anticancer drugs. These findings indicate that expression of HSPs can negatively regulate the effectiveness of cytotoxic drugs. We conducted experiments to study the regulation of expression of heat shock proteins (HSPs) in human breast cancer MCF-7 cells exposed to heat shock by intracellular free Ca2+ and protein kinase C. Cells exposed to 44 degrees C for 20 min displayed increased expression of HSP-72 and GRP-94, that reached a maximum 4-5 h later and returned to baseline levels within 24 h. Levels of HSP-72 mRNA in cells exposed to heat shock increased, suggesting that the heat-induced increase in HSP-72 occurs at the transcriptional level. The synthesis of HSP-72 but not GRP-94 was inhibited when cells were exposed to heat shock in medium devoid of Ca2+ and attenuated by more than 50% when cells were pretreated with the calcium chelator BAPTA for 30 min prior to heat shock. HSP-72 synthesis was enhanced when cells were treated with the protein kinase C inhibitor, GF-109203X. These data indicate that Ca2+ and PKC are involved in regulation of HSP-72 synthesis. However, removal of external Ca2+ and treatment with BAPTA, GF-109203X, or exposure to sublethal heat shock protected cells from subsequent thermal injury. The intracellular free calcium concentration ([Ca2+]i) in resting fura-2-loaded MCF-7 cells was 156 +/- 16 nM (n = 29). Heat shock increased [Ca2+]i in a time- and temperature-dependent manner. Exposure of cells to 44 degrees C for 20 min increased [Ca2+]i by 234 +/- 13%, which subsequently returned to baseline levels within 120 min. Removal of external Ca2+ eliminated the increase, indicating that the increase in [Ca2+]i was due to Ca2+ influx. Pretreatment of the cells with BAPTA or GF-109203X for 30 min or a sublethal heat shock to allow HSP-72 overexpression led to an attenuation of the increase in [Ca2+]i by a subsequent heat shock. The results suggest that HSP-72 but not GRP-94 is regulated by [Ca2+]i and PKC activity. The cytoprotection produced by chelation of Ca2+, GF-109203X, or HSP-72 overexpression is probably due to their ability to attenuate the [Ca2+]i response to heating.
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PMID:Biochemical requirements for the expression of heat shock protein 72 kda in human breast cancer MCF-7 cells. 1054 66

Migration studies suggest that the high incidence of postmenopausal breast cancer in Western women is related mainly to epigenetic factors. Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) also appears to involve environmental rather than genetic factors, and a role has been postulated for metabolic-endocrine changes related to the Western lifestyle. Protein kinase C (PKC) is important in cell signal transduction, and laboratory studies show that PKC stimulates the activities of urokinase plasminogen activator, matrix metalloproteinases and cell adhesion molecules, all of which are known to increase invasiveness in human mammary cancer cell lines. In rodents, the activity of PKC in tissue cells is enhanced by insulin, and PKC isoenzymes have been shown to stimulate the development of hyperinsulinaemic insulin resistance in rodents. Clinically, hyperinsulinaemia and the concomitant increase in circulating levels of free oestradiol and bioactive insulin-like growth factor 1 (IGF1) are each confirmed markers of high risk for breast cancer in women. Lesions of DCIS show evidence of regression with mammary involution, but it is postulated that this may be opposed by the concomitants of hyperinsulinaemic insulin resistance. The prevalence of the latter is increasing in Western populations, and a combination of high IGF1 and low IGF-binding protein 3 concentrations has been associated with the presence of DCIS lesions in premenopausal women. Measures that enhance insulin sensitivity in such women may reduce the risk of progression in DCIS lesions, and a clinical trial is proposed to test the hypothesis.
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PMID:Biological mechanisms in breast cancer invasiveness: relevance to preventive interventions. 1083 May 73

Protein kinase C (PKC) comprises a family of ubiquitously expressed phospholipid-dependent enzymes that regulate cell growth and differentiation. Several effectors that modify mammary cell biology work at least partially through PKC-dependent pathways. Studies with mammary epithelial cells and tissues have demonstrated probable roles for the PKCs in processes associated with carcinogenesis including proliferation, estrogen sensitivity, and apoptosis. The involvement of PKCs in this wide variety of responses may in part be explained by the expression of multiple PKCs in breast tissue and the possibility that individual PKCs selectively phosphorylate different proteins and preferentially mediate different biological responses. Further understanding of the role of individual PKCs in mammary cell growth and tumor promotion/progression is likely to lead to new insights for breast cancer diagnosis and treatment.
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PMID:Protein kinase C isozymes and substrates in mammary carcinogenesis. 1088 91

The protein kinase B/Akt serine/threonine kinase, located downstream of phosphoinositide 3-kinase (PI-3K), is a major regulator of cellular survival and proliferation. Atypical protein kinase C (aPKC) family members are activated by PI-3K and also contribute to cell proliferation, suggesting that Akt and aPKC might interact to activate signalling through the PI-3K cascade. Here we demonstrate that blocking PKC activity in MDA-MB-468 breast cancer cells increased the phosphorylation and activity of Akt. Functional PI-3K was required for the PKC inhibitors to increase Akt phosphorylation and activation, potentially owing to the activation of specific PKC isoforms by PI-3K. The concentration dependence of the action of the PKC inhibitors implicates aPKC in the inhibition of Akt phosphorylation and activity. In support of a role for aPKC in the regulation of Akt, Akt and PKCzeta or PKClambda/iota were readily co-precipitated from the BT-549 breast cancer cell line. Furthermore, the overexpression of PKCzeta inhibited growth-factor-induced increases in Akt phosphorylation and activity. Thus PKCzeta associates physically with Akt and decreases Akt phosphorylation and enzyme activity. The effects of PKC on Akt were transmitted through the PI-3K cascade as indicated by changes in p70 s6 kinase (p70(s6k)) phosphorylation. Thus PKCzeta, and potentially other PKC isoenzymes, regulate growth-factor-mediated Akt phosphorylation and activation, which is consistent with a generalized role for PKCzeta in limiting growth factor signalling through the PI-3K/Akt pathway.
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PMID:Inhibition of growth-factor-induced phosphorylation and activation of protein kinase B/Akt by atypical protein kinase C in breast cancer cells. 1108 41

We have compared several breast cancer cell lines that differ in their responsiveness to TNF to determine the involvement of PKC isozymes in regulating sensitivity of breast cancer cells to TNF. While MCF-7 and BT-20 cells were responsive to TNF without any metabolic inhibitors, CAMA-1 and SKBR-3 cells responded to TNF in the presence of cycloheximide; MDA-MB-231 and Hs578t cells were resistant to TNF even in the presence of cycloheximide. Bisindolylmaleimide (BIM), an inhibitor of PKC, either alone (MCF-7 and BT-20) or in combination with cycloheximide enhanced sensitivity of these cells to TNF. The PKC isozyme profile of MCF-7 cells was similar to BT-20 cells and that of CAMA-1 cells was similar to SKBR-3 cells. MCF-7, BT-20 and MDA-MB-231 cells that were most responsive to BIM-mediated sensitization to TNF contained relatively high level of PKC epsilon and proteolytic cleavage of PKC epsilon correlated with TNF-induced cell death. BIM did not inhibit NF-kappa B activation by TNF but caused activation of caspases and enhanced cleavage of PKC delta and -epsilon. These results suggest that proteolytic cleavage of PKC epsilon may be associated with PKC inhibitor mediated sensitization of breast cancer cells to TNF.
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PMID:Differential sensitivity of breast cancer cells to tumor necrosis factor-alpha: involvement of protein kinase C. 1116 6

Ebp1, a 47 kDa ubiquituously expressed protein, binds the ErbB3 receptor in human serum starved breast cancer cell lines and dissociates from ErbB3 on treatment with the ErbB3 ligand, Heregulin (HRG). However, the mechanism of Ebp1-ErbB3 association/dissociation is not understood. Since Ebp1 contains six putative Protein Kinase C serine/threonine phosphorylation sites, we examined the ability of PKC to phosphorylate Ebp1 and to regulate Ebp1-ErbB3 binding. We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. However, HRG-induced phosphorylation of Ebp1 occurred predominantly in a PKC-independent manner. The ability of Ebp1 to associate with ErbB3 in serum-starved NIH3T3 cells overexpresssing ErbB3 was abrogated by treating cells with a PKC inhibitor. These findings suggest that PKC plays a role in regulating phosphorylation and function of Ebp1 in vivo.
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PMID:Regulation of the ErbB3 binding protein Ebp1 by protein kinase C. 1132 28

The biochemical path for the activation of ErbB-2 by PKC activator was investigated in MDA-MB-231 human breast cancer cells. We found that PMA-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) increased its binding with Tob that exerts an anti-proliferative effect through the binding with ErbB-2. The phosphorylation site domain (PSD) of MARCKS was relevant to its interaction with Tob. Decreased binding of Tob with ErbB-2 and subsequent activation of ErbB-2 were observed in MDA-MB-231 cells in response to PMA treatment. The present study proposes that MARCKS phosphorylation by PKC removes Tob from ErbB-2 by increasing its binding affinity with Tob, and thereby activates the ErbB-2 mediated signal transduction.
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PMID:Tob-mediated cross-talk between MARCKS phosphorylation and ErbB-2 activation. 1132 93

The 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in several human cancer cell lines and in normal human mammary and prostatic epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the Stat6-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. As a matter of fact, we have shown that IL-4-activated Stat6 in all cell lines studied, where IL-4 induced 3beta-HSD type 1 expression but not in those cell lines that failed to respond to IL-4. The mechanism of the induction of 3beta-HSD type 1 gene expression was further characterized in ZR-75-1 human breast cancer cells. We have also found that IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in these cell lines. Moreover, insulin-like growth factor (IGF)-1 and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2 domain-containing proteins, leading to the activation of multiple pathways, such as the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein (MAP) pathways. The inhibition of IL-4-induced 3beta-HSD expression by PI 3-kinase inhibitors (wortmannin and LY294002) as well as an inhibitor of MAP kinase activation (PD98059), indicates the involvement of those pathways in this response to IL-4. Wortmannin also blocked MAP kinase activation by IL-4, insulin and IGF-1 suggesting that the MAP kinase cascade acts as a downstream effector of PI 3-kinases. Furthermore, we showed that the PKC activator phorbol-12-myristate-13-acetate (PMA) also potentiated the IL-4-induced 3beta-HSD activity, thus suggesting that one signaling molecule that is involved in the signal transduction of the IL-4 action on 3beta-HSD type 1 expression is also a substrate for PKC. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involve in the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAP kinase-dependent signaling pathway. However, the inability of IGF-1, insulin and PMA to stimulate 3beta-HSD type 1 expression by themselves in the absence of IL-4 indicates that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with an IL-4-specific signaling molecule, such as the transcription factor Stat6. It is also of interest to note that there also appear to be differences between the regulation of the 3beta-HSD type 1 and type 2 promoters.
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PMID:Multiple signal transduction pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase in normal and tumoral target tissues. 1138 80

Protein kinase C (PKC) is known to activate NF-kappaB whereas the lipid mediator ceramide was recently shown to inhibit activation of this transcription factor (1, 2). In this study, the mechanisms by which ceramide interferes with this pathway were examined in Jurkat leukemia and MCF-7 breast cancer cells. Both exogenous and endogenous ceramide inhibited selectively PKC-mediated activation of NF-kappaB by reverting PKC translocation to the membrane. Next, confocal and immunofluorescence studies were performed to evaluate the direct effects of ceramide on PKC. These studies showed that ceramide inhibited translocation of a green fluorescent protein (GFP)-PKCbeta2 fusion protein in response to PMA. A mutant PKC in which autophosphorylation sites were mutated to alanine (PKC-DA) was resistant to ceramide. A kinase-inactive mutant (PKC-KR) was also resistant to ceramide action, and the results were supported using kinase inhibitors of the enzyme. Finally, overexpression of PKC-DA prevented, at least partly, the ability of ceramide to inhibit activation of NF-kappaB. Taken together, these studies show that ceramide has acute effects on translocation of PKC by inducing reverse translocation, and this reversal requires both the kinase activity of PKC and phosphorylation of the autophosphorylation sites.
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PMID:Ceramide inhibition of NF-kappaB activation involves reverse translocation of classical protein kinase C (PKC) isoenzymes: requirement for kinase activity and carboxyl-terminal phosphorylation of PKC for the ceramide response. 1168 65

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