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)

Caveolin-1 is an essential structural constituent of caveolae which is involved in regulation of mitogenic signaling and oncogenesis. Caveolin-1 has been implicated in cell migration but its exact role and mechanism of action in this process remained obscure. We have previously reported that expression of caveolin-1 in stably transfected MCF-7 human breast cancer (MCF-7/Cav1) cells up-regulates phosphorylation of a putative Akt substrate protein, designated pp340 [D. Ravid, S. Maor, H. Werner, M. Liscovitch, Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling, Oncogene 24 (2005) 1338-1347.]. We now show, using differential detergent extraction, SDS-PAGE and mass spectrometry, that the major protein in the pp340 band is the actin filament cross-linking protein filamin A. The identity of pp340 as filamin A was confirmed by immunoprecipitation of pp340 with specific filamin A antibodies. RT-PCR, flow cytometry and Western blot analyses show that filamin A mRNA and protein levels are respectively 3.5- and 2.5-fold higher in MCF-7/Cav1 cells than in MCF-7 cells. Basal filamin A phosphorylation on Ser-2152, normalized to total filamin A levels, is 7.8-fold higher in MCF-7/Cav1 than in MCF-7 cells. Insulin-like growth factor-I (IGF-I) stimulates phosphorylation of filamin A on Ser-2152 in MCF-7 cells and further enhances Ser-2152 phosphorylation over its already high basal level in MCF-7/Cav1 cells. The effect of IGF-I is inhibited by the PI3K inhibitor wortmannin, indicating that IGF-I-stimulated phosphorylation of filamin A occurs via the PI3K/Akt pathway. Co-immunoprecipitation experiments have confirmed a previous report showing that filamin A and caveolin-1 co-exist in a complex and have revealed the presence of active phospho-Akt in this complex. Ser-2152 phosphorylation of filamin A has been implicated in cancer cell migration. Accordingly, caveolin-1 expression dramatically enhances IGF-I-dependent MCF-7 cell migration. These data indicate that caveolin-1 specifies filamin A as a novel target for Akt-mediated filamin A Ser-2152 phosphorylation thus mediating the effects of caveolin-1 on IGF-I-induced cancer cell migration.
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PMID:Filamin A is a novel caveolin-1-dependent target in IGF-I-stimulated cancer cell migration. 1859 95

The type 1 TNFR (TNFR1) contains a death domain through which it interacts with other death-domain proteins to promote cellular responses. However, signaling through death-domain proteins does not explain how TNFR1 induces the tyrosine phosphorylation of intracellular proteins, which are important to cellular responses induced by TNFR1. In this study, we show that TNFR1 associates with Jak2, c-Src, and PI3K in various cell types. Jak2 and c-Src constitutively associate with and are constitutively active in the TNFR1 complex. Stimulation with TNF induces a time-dependent change in the level of Jak2, c-Src, and PI3K associated with TNFR1. The tyrosine kinase activity of the complex varies with the level of tyrosine kinase associated with TNFR1. TNFR1/c-Src plays a role in activating Akt, but not JNK or p38 MAPK, whereas TNFR1/Jak2 plays a role in activating p38 MAPK, JNK, and Akt. TNFR1/c-Src, but not TNFR1/Jak2, plays an obligate role in the activation of NF-kappaB by TNF, whereas TNFR1/Jak2, but not TNFR1/c-Src, plays an obligate role in the activation of STAT3. Activation of TNFR1 increased the expression of vascular endothelial growth factor, p21(WAF1/CIP1), and manganese superoxide dismutase in MCF7 breast cancer cells, and increased the expression of CCl2/MCP-1 and IL-1beta in THP-1 macrophages. Inhibitors of Jak2 and c-Src impaired the induction of each of these target proteins. These observations show that TNFR1 associates with and uses nonreceptor tyrosine kinases to engage signaling pathways, activate transcription factors, and modulate gene expression in cells.
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PMID:Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signaling pathways that regulate transcription factor activity. 1860 83

SLIT-2 is considered as a candidate tumor suppressor gene, because it is frequently inactivated in various cancers due to hypermethylation of its promoter region and allelic loss. However, the exact mechanism of its tumor-suppressive effect has not been elucidated. Here, we observed that Slit-2-overexpressing breast cancer cells exhibited decreased proliferation and migration capabilities compared with control cells under in vitro conditions. These results were confirmed in vivo in mouse model systems. Mice injected with MCF-7/Slit-2 cells showed a 60-70% reduction in tumor size compared with mice injected with MCF-7/VC cells both in the absence and presence of estrogen. Upon further elucidation, we observed that Slit-2 mediates the tumor-suppressive effect via a coordinated regulation of the beta-catenin and PI3K signaling pathways and by enhancing beta-catenin/E-cadherin-mediated cell-cell adhesion. Our study for the first time reveals that Slit-2-overexpressing breast cancer cells exhibit tumor suppressor capabilities through the novel mechanism of beta-catenin modulation.
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PMID:Slit-2 induces a tumor-suppressive effect by regulating beta-catenin in breast cancer cells. 1861 62

Inhibitors of the epidermal growth factor receptor (EGFR) have generated considerable hope for cancer treatment, specifically for lung and breast cancers. Therefore, identification of a natural, nontoxic agent(s) as an inhibitor of EGFR is of considerable importance. Delphinidin, an anthocyanidin present in pigmented fruits and vegetables, possesses potent antioxidant and antiproliferative properties. In our study, employing EGFR positive breast cancer AU-565 cells and immortalized MCF-10A cells, we evaluated the effect of delphinidin on EGFR and its downstream signaling pathways. Delphinidin (5-40 microM; 3 hr) treatment of both AU-565 cells and MCF-10A cells inhibited the (i) phosphorylation of EGFR, (ii) activation of PI3K, (iii) phosphorylation of AKT and MAPK. Further, delphinidin treatment of AU-565 cells inhibited EGF-induced autophosphorylation of EGFR, AKT and MAPK, activation of PI3K and cell invasion. We then compared the growth inhibitory effects of delphinidin (5-40 microM; 48 hr), and found that it resulted in a decrease in cell growth of AU-565 and MCF-10A cells but had only minimal effects on normal mammary epithelial 184A1 cells. Treatment of AU-565 cells with delphinidin resulted in (i) induction of apoptosis, (ii) cleavage of PARP protein, (iii) activation of caspase-3 and (iv) downregulation of Bcl-2 with an increase in the expression of Bax. In summary, our study identifies a naturally occurring dietary agent delphinidin as an effective inhibitor of EGFR signaling in breast cancer cells. We suggest that delphinidin could be developed as an agent for the management of EGFR positive human cancers.
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PMID:Inhibition of epidermal growth factor receptor signaling pathway by delphinidin, an anthocyanidin in pigmented fruits and vegetables. 1862 29

The majority of breast cancers are estrogen receptor (ER) positive and depend on estrogen for growth. Therefore, blocking estrogen mediated actions remains the strategy of choice for the treatment and prevention of breast cancer. The selective estrogen receptor modulators (SERMs) are molecules that block estrogen action in breast cancer, but can still potentially maintain the beneficial effects of estrogen in other tissues, such as bone and cardiovascular system. Tamoxifen, the prototypical drug of this class has been used extensively for the past 30 years to treat and prevent breast cancer. The target of drug action, ERs alpha and beta, are the two receptors which are responsible for the first step in estrogen and SERM action. The SERM binds to the ERs and confers a unique conformation to the complex. In a target site which expresses antiestrogenic actions, the conformation of the ER is distinctly different from estrogen bound ER. The complex recruits protein partners called corepressors to prevent the transcription of estrogen responsive genes. In contrast, at a predominantly estrogenic site coactivators for estrogen action are recruited. Unfortunately at an antiestrogenic site such as breast cancer, long term SERM therapy causes the development of acquired resistance. The breast and endometrial tumor cells selectively become SERM stimulated. Overexpression of receptor tyrosine kinases, HER-2, EGFR and IGFR and the signaling cascades following their activation are frequently involved in SERM resistant breast cancers. The aberrantly activated PI3K/AKT and MAPK pathways and their cross talk with the genomic components of the ER action are implicated in SERM resistance. Other down stream factors of HER-2 and EGFR signaling, such as PI3K/AKT, MAPK or mTOR pathways has also been found to be involved in resistance mechanisms. Blocking the actions of HER-2 and EGFR represent a rational strategy for treating SERM resistant phenotypes and may in fact restore the sensitivity to the SERMs. Another approach exploits the discovery that low dose estrogen will induce apoptosis in the SERM resistant breast cancers. Numerous clinical studies are addressing these issues.
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PMID:Selective estrogen modulators as an anticancer tool: mechanisms of efficiency and resistance. 1863 93

In a breast tumor xenograft model, the MCT-1 oncogene increases the in vivo tumorgenicity of MCF7 cells by promoting angiogenesis and inhibiting apoptosis. Increases in the tumor microvascular density are accompanied by a strong reduction in the levels of the angiogenesis inhibitor thrombospondin-1 (TSP1), but the mechanisms underlying this process are unknown. We show that TSP1 expression is controlled, at least in part, by post-transcriptional events. Using RNA interference to knock down the expression of the RNA-binding protein HuR in MCF7 cells as well as HuR overexpression, we demonstrate that HuR plays an important role in translation of the TSP1 mRNA. Furthermore, employing the RIP-Chip assay yielded 595 transcripts with significantly altered binding to HuR in the more tumorigenic breast cancer clones compared with the weakly tumorigenic clones. These mRNAs clustered in several pathways implicated in the transformed phenotype, such as the RAS pathway (involved in mitogenesis), the PI3K pathway (evasion of apoptosis) and pathways mediating angiogenesis and the cellular response to hypoxia. These findings demonstrate for the first time that global changes in HuR-bound mRNAs are implicated in the evolution to a more tumorigenic phenotype in an in vivo tumor model and underscore the role of global mRNA-protein interactions toward tumor progression.
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PMID:Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype. 1864 87

Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells and induce the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia. In this study, under hypoxic conditions (1% O(2)), we examined the effect of quercetin on the intracellular level of HIF-1alpha and extracellular level of vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Surprisingly, we observed that quercetin suppressed the HIF-1alpha accumulation during hypoxia in human prostate cancer LNCaP, colon cancer CX-1, and breast cancer SkBr3 cells. Quercetin treatment also significantly reduced hypoxia-induced secretion of VEGF. Suppression of HIF-1alpha accumulation during treatment with quercetin in hypoxia was not prevented by treatment with 26S proteasome inhibitor MG132 or PI3K inhibitor LY294002. Interestingly, hypoxia (1% O(2)) in the presence of 100 microM quercetin inhibited protein synthesis by 94% during incubation for 8 h. Significant quercetin concentration-dependent inhibition of protein synthesis and suppression of HIF-1alpha accumulation were observed under hypoxic conditions. Treatment with 100 microM cycloheximide, a protein synthesis inhibitor, replicated the effect of quercetin by inhibiting HIF-1alpha accumulation during hypoxia. These results suggest that suppression of HIF-1alpha accumulation during treatment with quercetin under hypoxic conditions is due to inhibition of protein synthesis.
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PMID:Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) through inhibiting protein synthesis. 1865 83

Her-2/neu (ErbB2) is a transmembrane tyrosine kinase and acts as a co-receptor for the other EGFR family members. It is well known that high expression of Her-2/neu is associated with a poor prognosis in breast cancer. Quercetin, a flavonoid present in many vegetables and fruits, has been studied extensively as a chemoprevention agent in several cancer models. In this study, we observed that quercetin decreased the level of Her-2/neu protein in time- and dose-dependent manners and also inhibited the downstream survival PI3K-Akt signaling pathway in Her-2/neu-overexpressing breast cancer SK-Br3 cells. We also observed that quercetin induced polyubiquitination of Her-2/neu. When the proteasome pathway was blocked by MG-132 during quercetin treatment, accumulation of the NP-40 insoluble form of Her-2/neu occurred. Interestingly, data from immunocomplex studies revealed that quercetin promoted interaction between Her-2/neu and Hsp90 which is a molecular chaperone involved in stabilization of Her-2/neu. In this condition, inhibition of Hsp90 activity by a specific inhibitor, geldanamycin (GA), or intracellular ATP depletion caused dissociation of Hsp90 from Her-2/neu and promoted ubiquitination and down-regulation of Her-2/neu protein. In addition, the carboxyl terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, played a crucial role in the quercetin-induced ubiquitination of Her-2/neu. Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could indicate an lateration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu. We believe that by using quercetin, new therapeutic strategies can be developed to treat Her-2/neu overexpressing cancers.
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PMID:Quercetin-induced ubiquitination and down-regulation of Her-2/neu. 1865 87

Mammalian target of rapamycin (mTOR) is a component of a signaling pathway (PTEN/PI3K/AKT) that is frequently dysregulated in cancer. However, its precise relationship to the MAPK cascade (Ras/Raf/MEK/ERK), another pathway often implicated in tumorigenesis, has not been well defined. Recent evidence from tissue specimens obtained from patients who have received mTOR inhibitors suggests that ERK may be activated in response to mTOR interruption. In this issue of the JCI, Waugh Kinkade et al. and Carracedo et al. examine the relationship between these pathways in prostate and breast cancer cell model systems (see the related articles beginning on pages 3051 and 3065, respectively). Their findings suggest a link between inhibition of mTOR and ERK activation, possibly reflecting interruption of a novel negative S6K1-dependent feedback loop. Significantly, both groups observed that simultaneous inhibition of MEK/ERK and mTOR resulted in substantially enhanced antitumor effects both in vitro and in vivo. Together, these findings suggest that concurrent interruption of complementary signaling pathways warrants further investigation in cancer therapy.
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PMID:Cotargeting survival signaling pathways in cancer. 1872 89

Expression of the chemokine receptor CXCR4, a G protein-coupled receptor, and HER2, a receptor tyrosine kinase, strongly correlates with the aggressive and metastatic potential of breast cancer cells. We studied estrogen regulation of CXCR4 in estrogen receptor (ER)-positive MCF-7 breast cancer cells overexpressing HER2 (MCF7-HER2). Although estrogen evoked no change in CXCR4 mRNA levels, CXCR4 protein was significantly up-regulated after estrogen treatment of these cells, whereas estrogen had no effect on CXCR4 protein level in parental MCF7 cells that are low in HER2. Use of the CXCR4 specific inhibitor, AMD 3100, indicated that this increase in CXCR4 protein was partially responsible for the increase in estrogen-induced migration of these cells. The estrogen-induced increase in CXCR4 protein in MCF-7-HER2 cells was abrogated by the antiestrogen ICI 182780 and by gefitinib (Iressa; a phospho-tyrosine kinase inhibitor), indicating an ER-mediated effect and confirming involvement of receptor tyrosine kinases, respectively. Using specific pathway inhibitors, we show that the estrogen-induced increase in CXCR4 involves PI3K/AKT, MAPK and mTOR pathways. PI3K/AKT and MAPK pathways are known to result in the phosphorylation and functional inactivation of tuberin (TSC2) of tuberous sclerosis complex thereby negating its inhibitory effects on mTOR, which in turn stimulates the translational machinery. Small interfering RNA (siRNA) mediated knockdown of tuberin elevated the level of CXCR4 protein in MCF7-HER2 cells and also nullified further estrogen up-regulation of CXCR4. This study suggests a pivotal role of PI3 K, MAPK and mTOR pathways, via tuberin, in post-transcriptional control of CXCR4, initiated through estrogen-stimulated crosstalk between ER and HER2. Thus, post-transcriptional regulation of CXCR4 by estrogens acting through ER via kinase pathways may play a critical role in determining the metastatic potential of breast cancer cells.
Breast Cancer Res Treat 2009 Sep
PMID:Post-transcriptional regulation of chemokine receptor CXCR4 by estrogen in HER2 overexpressing, estrogen receptor-positive breast cancer cells. 1880 77


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