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 Bmi-1 oncogene is overexpressed in a number of malignancies including breast cancer. In addition to Bmi-1, mammalian cells also express four other polycomb group (PcG) proteins that are closely related to Bmi-1. Virtually nothing is known about the role of these PcG proteins in oncogenesis. We have recently reported that Mel-18, a Bmi-1-related PcG protein, negatively regulates Bmi-1 expression, and that its expression negatively correlates with Bmi-1 in proliferating and senescing human fibroblasts. Here, we report that the expression of Bmi-1 and Mel-18 inversely correlates in a number of breast cancer cell lines and in a significant number of breast tumor samples. Overexpression of Mel-18 results in repression of Bmi-1 and reduction of the transformed phenotype in malignant breast cancer cells. Furthermore, the repression of Bmi-1 by Mel-18 is accompanied by the reduction of Akt/protein kinase B (PKB) activity in breast cancer cells. Similarly, Bmi-1 knockdown using RNA interference approach results in down-regulation of Akt/PKB activity and reduction in transformed phenotype of MCF7 cells. Importantly, we show that overexpression of constitutively active Akt overrides tumor-suppressive effect of Mel-18 overexpression and the knockdown of Bmi-1 expression. Thus, our studies suggest that Mel-18 and Bmi-1 may regulate the Akt pathway in breast cancer cells, and that Mel-18 functions as a tumor suppressor by repressing the expression of Bmi-1 and consequently down-regulating Akt activity.
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PMID:Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and down-regulating Akt activity in breast cancer cells. 1754 84

A growing number of clinically relevant molecular and cellular responses are observed following photodynamic therapy (PDT). PDT-mediated oxidative stress and PDT-induced tissue hypoxia can elicit the transcriptional and/or translational expression of genes associated with cellular stress, inflammation, angiogenesis, immuno-modulation, apoptosis and signal transduction. One of the signaling molecules activated by oxidative stress is Akt/protein kinase B. Phosphorylation of Akt/protein kinase B activates this signaling molecule and induces a survival response in effected cells and tissue. We hypothesized that PDT using Photofrin (PH) as the photosensitizer could also induce increased levels of Akt phosphorylation. Results from our initial set of experiments demonstrated that in vitro and in vivo PDT treatments induced Akt phosphorylation. Interestingly, incubation of mouse and human breast cancer cells with the porphyrin-based photosensitizer, PH, increased the expression of Akt phosphorylation in the absence of light. Exposure of the corresponding mouse and human-derived breast cancer tumors growing in mice to 630 nm light in the absence of PH administration also induced Akt phosphorylation. These results demonstrate that individual components of the PDT process, photosensitizer alone and light alone, as well as the complete PDT procedure can activate the Akt signaling pathway.
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PMID:Multiple components of photodynamic therapy can phosphorylate Akt. 1788 Apr 96

2-Deoxyglucose (2-DG), which has been shown to inhibit mammary carcinogenesis, was used as a metabolic probe to investigate effects of limiting energy availability (reduced cellular ATP) on patterns of proteins' phosphorylation that play a role in the development of cancer. Experiments were conducted using a human breast cancer cell line, MDA-MB-468, and 1-methyl-1-nitrosourea-induced rat model for mammary carcinogenesis. Under in vitro conditions in which cellular ATP concentration decreased rapidly with increasing 2-DG in a dose and time dependent manner, levels of phosphorylated mammalian target of rapamycin (P-mTOR) decreased in parallel to decreases in ATP concentration. Concomitantly, phosphorylation of two upstream regulators of mTOR, AMP-activated protein kinase (AMPK) and Akt/protein kinase B were increased and decreased, respectively, with increased levels of phosphorylated acetyl-CoA carboxylase as an indicator of AMPK activation. Levels of insulin like growth factor 1-receptor and phosphoinositide-3 kinase p110 alpha were also reduced. Similar effects were observed in mammary carcinomas in vivo at concentration of 0.03% (w/w) dietary 2-DG that inhibited carcinogenesis. In vitro, downregulation of mTOR was accompanied by decreases in phosphorylation of two of mTOR's targets, 70-kDa ribosomal protein S6 kinase and eukaryote initiation factor 4E binding protein 1. Glucose treatment reversed 2-DG effects. When cells were transfected with dominant-negative AMPK alpha 2, effects of 2-DG on mTOR and its downstream effectors were diminished, providing evidence of a link between AMPK and mTOR when energy availability was limited. This work indicates that AMPK, Akt, and mTOR are candidate targets for efforts to inhibit the carcinogenic process by limiting energy availability.
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PMID:Modulation of the activities of AMP-activated protein kinase, protein kinase B, and mammalian target of rapamycin by limiting energy availability with 2-deoxyglucose. 1824 80

Insulin-like growth factor (IGF)-II is a required intermediate for prolactin-induced up-regulation of cyclin D1 and proliferation in normal murine mammary epithelial cells in vivo and in vitro. However, we have recently shown that prolactin can rapidly induce cyclin D1 protein expression and subsequent proliferation in the MCF-7 human breast cancer cell line, suggesting that prolactin actions can be independent of IGFs in breast disease. Here, we investigate the relationship between these factors and show that prolactin up-regulated transcript levels of both IGF-I and IGF-II, but only after increases in cyclin D1 protein were observed. Moreover, prolactin increased cyclin D1 in the presence of the IGF-I receptor neutralizing antibody alphaIR3. However, on cotreatment, IGF-I and prolactin elicited cooperative phosphorylation of extracellular signal-regulated kinases 1 and 2 and protein kinase B/AKT, but not signal transducer and activator of transcription 5. This interaction extended to increased activation of activating protein-1 enhancer elements, phosphorylation of glycogen synthase kinase 3beta, induction of cyclin D1, and ultimately, increased cell number. It also increased invasive behavior, which correlated with elevated matrix metalloproteinase-2 transcript levels. Interestingly, prolactin augmented phosphorylation at Tyr(1135) and Tyr(1136) of IGF-I receptor on cotreatment with IGF-I, although prolactin alone had no effect. Together, these data indicate that strong cooperative cross talk between prolactin and IGF-I augments biological processes associated with neoplastic progression, with implications for therapeutic strategies.
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PMID:Prolactin does not require insulin-like growth factor intermediates but synergizes with insulin-like growth factor I in human breast cancer cells. 1840 42

The PI3K (phosphoinositide 3-kinase) pathway regulates cell proliferation, survival and migration and is consequently of great interest for targeted cancer therapy. Using a panel of small-molecule PI3K isoform-selective inhibitors in a diverse set of breast cancer cell lines, we have demonstrated that the biochemical and biological responses were highly variable and dependent on the genetic alterations present. p110alpha inhibitors were generally effective in inhibiting the phosphorylation of PKB (protein kinase B)/Akt and S6, two downstream components of PI3K signalling, in most cell lines examined. In contrast, p110beta-selective inhibitors only reduced PKB/Akt phosphorylation in PTEN (phosphatase and tensin homologue deleted on chromosome 10) mutant cell lines, and was associated with a lesser decrease in S6 phosphorylation. PI3K inhibitors reduced cell viability by causing cell-cycle arrest in the G(1) phase, with multi-targeted inhibitors causing the most potent effects. Cells expressing mutant Ras were resistant to the cell-cycle effects of PI3K inhibition, which could be reversed using inhibitors of Ras signalling pathways. Taken together, our data indicate that these compounds, alone or in suitable combinations, may be useful as breast cancer therapeutics, when used in appropriate genetic contexts.
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PMID:A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. 1849 48

Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with activated factor VII (FVIIa). TF is constitutively expressed in a variety of tumor cells and has been implicated in cellular signaling, angiogenesis, and tumor progression. Formation of TF-FVIIa complex and generation of downstream coagulation proteases, including activated factor X (FXa) and thrombin, initiate signaling by activation of protease-activated receptors (PARs). We have previously shown that TF-FVIIa-Xa complex formation promotes phosphorylation of p44/42 mitogen-activated protein kinase and Akt/protein kinase B in human breast cancer cells. In the present study, we show that formation of TF-FVIIa-FXa complex induces phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6 kinase in a human breast cancer cell line, Adr-MCF-7. Activation of the mTOR pathway, which is probably mediated by PAR1 and/or PAR2, was associated with enhanced cell migration, a key step in the metastatic cascade. Inhibition of this pathway with the specific mTOR inhibitor, rapamycin, markedly decreased cell migration induced by formation of TF-FVIIa-FXa complex. These studies suggest that TF-FVIIa-mediated signaling modulates mTOR pathway activation, which regulates in part breast cancer cell migration. Targeting the TF-mediated cell signaling pathway might represent a novel strategy for the treatment of breast cancer.
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PMID:Formation of tissue factor-factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells. 1861 47

Estrogen receptor alpha (ERalpha) is a well-known target for signaling pathways originating from growth factor receptors. Reactive oxygen species (ROS) can induce activation of extracellular response kinase 1/2 (Erk1/2) and protein kinase B (Akt). Both kinases have been implicated in the phosphorylation of serine 118 and serine 167 on ERalpha, respectively. This activity may lead either to ligand-independent activation of ERalpha or down-regulation of ERalpha and may contribute to development of the resistance to endocrine therapy. Treatment of MCF-7 human breast cancer cells with glucose oxidase (GO, 0.1 un/ml) induced transient phosphorylation of serine 118 and serine 167. The increase in expression of p-ser118-ERalpha was 355 +/- 98% (mean +/- SD) and of p-ser167-ERalpha was 632 +/- 355%. These effects were enhanced in Her2 over-expressing MCF7 cells. ERalpha expression declined to 63 +/- 20% within the first 90 min of treatment and was below 10% 24 h later. ROS induced phosphorylation of ERalpha resulted in decreased expression of pS2 and progesterone receptor. Activation of Erk1/2 and Akt was transient with highest levels of Erk1/2 being 595 +/- 143% and p-Akt 311 +/- 125%. Inhibition of Erk1/2 by U0126 (10 microM) decreased p-ser118-ERalpha by 51.7 +/- 8.5% and decreased p-ser167-ERalpha by 41.9 +/- 16.9% whereas inhibition of Akt by LY294002 (20 microM) and wortmannin (500 nM) or by siRNA knock-down, had no effect on p-ser167-ERalpha expression. Our data show for the first time that ROS can induce post-translational modifications of ERalpha at serine 118 and serine 167, and may lead to ERalpha down-regulation in human breast cancer cells. Both the phosphorylation and consequent down-regulation of ERalpha may be a mechanism associated with development of endocrine therapy resistance.
Breast Cancer Res Treat 2009 Nov
PMID:Reactive oxygen species induce phosphorylation of serine 118 and 167 on estrogen receptor alpha. 1894 90

Tumor protein D52 (TPD52) is a protein found to be overexpressed in prostate and breast cancer due to gene amplification. However, its physiological function remains under investigation. In the present study, we investigated the response of the LNCaP human prostate carcinoma cell line to deregulation of TPD52 expression. Proteomic analysis of prostate biopsies showed TPD52 overexpression at the protein level, whereas its transcriptional upregulation was demonstrated by real-time PCR. Transfection of LNCaP cells with a specific small hairpin RNA giving efficient knockdown of TPD52 resulted in significant cell death of the carcinoma LNCaP cells. As demonstrated by activation of caspases (caspase-3 and -9), and by the loss of mitochondrial membrane potential, cell death occurs due to apoptosis. The disruption of the mitochondrial membrane potential indicates that TPD52 acts upstream of the mitochondrial apoptotic reaction. To study the effect of TPD52 expression on cell proliferation, LNCaP cells were either transfected with enhanced green fluorescence protein-TPD52 or a specific small hairpin RNA. Enhanced green fluorescence protein-TPD52 overexpressing cells showed an increased proliferation rate, whereas TPD52-depleted cells showed the reverse effect. Additionally, we demonstrate that exogenous expression of TPD52 promotes cell migration via alphav beta3 integrin in prostate cancer cells through activation of the protein kinase B/Akt signaling pathway. From these results, we conclude that TPD52 plays an important role in various molecular events, particularly in the morphological diversification and dissemination of prostate carcinoma cells, and may be a promising target with respect to developing new therapeutic strategies to treat prostate cancer.
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PMID:Altered expression of tumor protein D52 regulates apoptosis and migration of prostate cancer cells. 1895 55

Tamoxifen is one of the most prescribed anti-breast-cancer drugs, but tumours becoming resistant hinder its efficacy in the clinic. There is therefore great interest in developing strategies to reduce resistance and sensitize breast cancer cells to tamoxifen. A groundbreaking study by Iorns et al. published in this issue of the Biochemical Journal suggests that a signal transduction pathway controlled by PDK1 (phosphoinositide-dependent kinase 1) plays a crucial role in regulating the sensitivity of breast cancer cells to tamoxifen. The implications of this study are that PDK1 or PI3K (phosphoinositide 3-kinase), Akt (also known as protein kinase B), S6K (S6 kinase) and mTOR (mammalian target of rapamycin) inhibitors, already being developed for cancer therapy, are likely to have additional utility in sensitizing breast tumours to tamoxifen. In this commentary we also discuss the possibility that inhibiting the PDK1 pathway may help overcome acquired resistance to other anti-cancer treatments.
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PMID:New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen. 1897 39

The phosphoinositide 3-kinase (PI3K) pathway regulates a multitude of cellular processes. Deregulation of PI3K signaling is often observed in human cancers. A major effector of PI3K is Akt/protein kinase B (PKB). Recent studies have pointed to distinct roles of Akt/PKB isoforms in cancer cell signaling. Studies have shown that Akt1 (PKBalpha) can attenuate breast cancer cell motility, whereas Akt2 (PKBbeta) enhances this phenotype. Here, we have evaluated the mechanism by which Akt1 blocks the migration of breast cancer cells through the transcription factor NFAT. A major effector of Akt/PKB is glycogen synthase kinase-3beta (GSK-3beta), also a NFAT kinase. Inhibition of GSK-3beta using short hairpin RNA or a selective inhibitor potently blocks breast cancer cell migration concomitant with a reduction in NFAT activity. GSK-3beta-mediated inhibition of NFAT activity is due to proteasomal degradation. Experiments using GSK-3beta mutants, which are unresponsive to Akt/PKB, reveal that inhibition of cell migration by Akt/PKB is mediated by GSK-3beta. These effects are recapitulated at the levels of NFAT degradation by the proteasome. Our studies show that activation of Akt/PKB leads to inactivation of the effector GSK-3beta and the outcome of this signaling event is degradation of NFAT by the proteasome and subsequent inhibition of cell migration.
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PMID:Akt/protein kinase b and glycogen synthase kinase-3beta signaling pathway regulates cell migration through the NFAT1 transcription factor. 1925 13


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