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)

Radiation therapy is a widely used treatment for metastatic bone cancer, but the rapid onset of tumor radioresistance is a major problem. We investigated the radiosensitizing effect of enzastaurin, a protein kinase Cbeta (PKCbeta) inhibitor, on bone tumor growth and tumor-related pain. We found that enzastaurin enhanced the effect of ionizing radiation on cultured murine 4T1 breast cancer and murine endothelial cells, suppressing their proliferation and colony formation. Enzastaurin and ionizing radiation also induced caspase-mediated apoptosis of 4T1 cells to a greater degree than radiation alone. Enzastaurin treatment of 4T1 cells blocked the phosphorylation of PKCbeta, as well as Ras and two of its downstream effectors ERK1/2 and RAL-GTP. Using an orthotopic model of bone metastasis, we observed that a combination of enzastaurin and localized radiation treatment reduced tumor blood vessel density, bone destruction and pain compared to single modality treatment. In conclusion, we demonstrate that inhibition of PKCbeta in combination with localized radiation treatment suppresses tumor growth and alleviates pain as compared to radiation-only treatment. We also show that the radiosensitizing effect of enzastaurin is associated with suppression of tumor cell proliferation and tumor-induced angiogenesis possibly through inhibition of the Ras pathway.
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PMID:Protein kinase C-beta inhibitor enzastaurin (LY317615.HCI) enhances radiation control of murine breast cancer in an orthotopic model of bone metastasis. 1780 85

Estrogen receptor alpha (ER alpha) is a ligand-activated transcription factor that regulates expression of estrogen-responsive genes. Upon binding of the ligand-occupied ER alpha to estrogen response elements (EREs) in DNA, the receptor interacts with a variety of coregulatory proteins to modulate transcription of target genes. We have isolated and identified a number of proteins associated with the DNA-bound ER alpha. One of these proteins, Rho guanosine diphosphate (GDP) dissociation inhibitor alpha (RhoGDI alpha), is a negative regulator of the Rho family of GTP-binding proteins. In this study, we demonstrate that endogenously expressed RhoGDI alpha is present in the nucleus as well as the cytoplasm of MCF-7 breast cancer cells, and that RhoGDI alpha binds directly to ER alpha, alters the ER alpha-ERE interaction, and influences the ability of ER alpha to regulate transcription of a heterologous estrogen-responsive reporter plasmid in transient transfection assays as well as endogenous, estrogen-responsive genes in MCF-7 cells. Our studies suggest that, in addition to the activity of RhoGDI alpha in the cytoplasm, it also influences ER alpha signaling in the nucleus.
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PMID:Rho GDP dissociation inhibitor alpha interacts with estrogen receptor alpha and influences estrogen responsiveness. 1790 65

RbAp48 is a WD-40 protein that plays an important role in chromatin metabolism and regulates Ras signaling. Here, we report that RbAp48 is involved in the regulation of cytoskeletal organization, a novel function. First, we show that transfection of RbAp48 into Hs-578T breast cancer cells (Hs-RbAp48-hi) leads to cell size reduction, a rounded cell shape, decreased cellular protrusions, and a higher nuclear/cytoplasmic ratio. Furthermore, we observed cytoskeletal F-actin organization disruption with loss of actin stress fibers and formation of membranous F-actin rings in Hs-RbAp48-hi cells. These morphologic changes were partially reversed by RbAp48 knockdown. Interestingly, mitogen-activated protein kinase (MAPK) was activated in Hs-RbAp48-hi cells, and this activity was also partly reversed by RbAp48 down-regulation. Furthermore, pharmacologic inhibition of MAPK led to the reappearance of organized actin fibers and focal contacts, suggesting MAPK as the effector pathway. Moreover, we show an increase in total Ras activity in Hs-RbAp48-hi cells with K-Ras-GTP becoming the dominant isoform. This reverted to baseline activity levels on RbAp48 small interfering RNA transfection, thus suggesting a direct role for RbAp48 in Ras regulation. Finally, we tested the model in transformed 3T3-K-Ras-G12V fibroblasts. As expected, RbAp48 knockdown in 3T3-K-Ras-hi fibroblasts resulted in reappearance of an organized cytoskeleton and shutdown of K-Ras activity. In conclusion, our data support a model whereby RbAp48 regulates cellular morphology and cytoskeletal organization by increasing K-Ras activity and signaling through MAPK.
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PMID:RbAp48 regulates cytoskeletal organization and morphology by increasing K-Ras activity and signaling through mitogen-activated protein kinase. 1797 74

The Ras-related, estrogen-regulated growth inhibitor (Rerg) is a Ras-related small GTPase and candidate tumor suppressor. Rerg gene expression is stimulated by the estrogen receptor alpha (ERalpha), and Rerg gene expression is absent in ER-negative breast cancers. ER-negative breast cancers are highly invasive and metastastic and are typically more advanced than their ER-positive counterparts. Like Ras, Rerg binds and hydrolyzes GTP, but unlike Ras, Rerg has been shown to possess growth inhibitory activity in breast cancer cells. The precise role that Rerg loss plays in breast cancer growth and the mechanisms by which it does so are unknown. This chapter describes tools used to detect and manipulate the expression of Rerg in breast cancer cells. We validate use of an antibody to detect Rerg expression. We describe the generation of expression vectors that encode wild-type and mutants of Rerg that are altered in GDP/GTP regulation. We also describe the development of an inducible Rerg expression system and of a retrovirus-based RNA interference approach to repress Rerg expression. These tools will be invaluable in evaluating the biological function of Rerg in breast cancer.
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PMID:Tools to study the function of the Ras-related, estrogen-regulated growth inhibitor in breast cancer. 1837 56

Galectin-3 (Gal-3) is a pleiotropic beta-galactoside-binding protein expressed at relatively high levels in human neoplasms. Its carbohydrate recognition domain (CRD) contains a hydrophobic pocket that can accommodate the farnesyl moiety of K-Ras. Binding of K-Ras to Gal-3 stabilizes K-Ras in its active (GTP-bound) state. Gal-3, which does not interact with N-Ras, was nevertheless shown to reduce N-Ras-GTP in BT-549 cells by an unknown mechanism that we explored here. First, comparative analysis of various cancer cell lines (glioblastomas, breast cancer cells and ovarian carcinomas) showed a positive correlation between low N-Ras-GTP/high K-Ras-GTP phenotype and Gal-3 expression levels. Next we found that epidermal growth factor-stimulated GTP loading of N-Ras, but not of K-Ras, is blocked in cells expressing high levels of Gal-3. Activation of Ras guanine nucleotide releasing proteins (RasGRPs) by phorbol 12-myristate 13-acetate (PMA) or downregulation of Gal-3 by Gal-3 shRNA increased the levels of N-Ras-GTP in Gal-3 expressing cells. We further show that the N-terminal domain of Gal-3 interacts with and inhibits RasGRP4-mediated GTP loading on N-Ras and H-Ras proteins. Growth of BT-549 cells stably expressing the Gal-3 N-terminal domain was strongly attenuated. Overall, these experiments demonstrate a new control mechanism of Ras activation in cancer cells whereby the Gal-3 N-terminal domain inhibits activation of N-Ras and H-Ras proteins.
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PMID:Galectin-3 regulates RasGRP4-mediated activation of N-Ras and H-Ras. 1841 34

The link between Ras transformation and enhanced cell migration due to altered integrin signaling is well established in tumorigenesis, however there remain gaps in our understanding of its mechanism. The Ras suppressor, Rsu-1, has recently been linked to the IPP (integrin-linked kinase {ILK}, PINCH-1/LIMS1, parvin) focal adhesion complex based on its interaction with the LIM 5 domain of PINCH1. Defining the role of the Rsu1-PINCH1-ILK-parvin complex in tumorigenesis is important because both ILK and PINCH1 are elevated in certain tumors while ectopic expression of Rsu-1 blocks tumorigenesis. Our studies previously identified an alternatively spliced isoform of Rsu-1 in high-grade gliomas. We report here the detection of a truncated (p29) Rsu-1 protein, which correlates with the presence of the alternatively spliced Rsu-1 RNA. This RNA and the respective protein were detected in human tumor cell lines that contain high levels of activated Ras, and inhibitor studies demonstrate that the Mek-ERK pathway regulates expression of this truncated Rsu-1 product. We also show that Rsu-1 co-localizes with ILK at focal contacts and co-immunoprecipitates with the ILK-PINCH1 complex in non-transformed cells, but following Ras transformation the association of Rsu-1 with the PINCH1-ILK complex is greatly reduced. Using a human breast cancer cell line, our in vitro studies demonstrate that the depletion of Rsu-1 full-length protein enhances cell migration coincident with an increase in Rac-GTP while the depletion of the p29 Rsu-1 truncated protein inhibits migration. These findings indicate that Rsu-1 may inhibit cell migration by stabilizing the IPP adhesion complex and that Ras activation perturbs this inhibitory function by modulating both Rsu-1 splicing and association of full-length Rsu-1 with IPP. Hence, our findings demonstrate that Rsu-1 links the Ras pathway with the IPP complex and the perturbations of cell attachment-dependent signaling that occur in the malignant process.
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PMID:The Rsu-1-PINCH1-ILK complex is regulated by Ras activation in tumor cells. 1843 35

Cytoskeleton rearrangement is necessary for tumor invasion and metastasis. Cellular molecules whose role is to regulate components of the cytoskeletal structure can dictate changes in cellular morphology. One of these molecules is the suppressor of tumor metastasis Nm23-H1. The level of Nm23-H1 expression has been linked to the invasiveness and metastatic potential of human cancers including melanoma and breast cancer. In this report, we demonstrate an interaction between the suppressor of tumor metastasis Nm23-H1, and Dbl-1, an oncoprotein which is associated with guanine exchange and belongs to a family of Guanine Exchange Factors (GEF). Nm23-H1 also was shown to bind pDbl which is the proto-oncoprotein of Dbl. Interestingly, the interaction between Nm23-H1 and Dbl-1 rescues the suppression of the cell motility activity Nm23-H1. Moreover, this interaction results in loss of the ability of the Dbl-1 oncoprotein to function as a GEF for the critical Rho-GTPase family member Cdc42. The loss of GTP loading onto Cdc42 resulted in a dramatic reduction in adhesion stimulated ruffles and suggests that Nm23-H1 can negatively regulate cell migration and tumor metastasis by modulating the activity of Cdc42 through direct interaction with Dbl-1.
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PMID:Nm23-H1 modulates the activity of the guanine exchange factor Dbl-1. 1847 Aug 81

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby Long Term Estradiol Deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response including up-regulation of ERalpha and the MAP kinase, PI-3-kinase and mTOR growth factor pathways. ERalpha is 4-10 fold up-regulated as a result of demethylation of its C promoter, This nuclear receptor then co-opts a classical growth factor pathway using SHC, Grb-2 and Sos. This induces rapid nongenomic effects which are enhanced in LTED cells. The molecules involved in the nongenomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha which physically associates with the adaptor protein SHC and induces its phosphorylation. In turn, SHC binds Grb-2 and Sos which results in the rapid activation of MAP kinase. These nongenomic effects ofestradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI-3-kinase and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-1 and EGF receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-1 receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, SHC and the IGF-1 receptor itself. SHC, after binding to ERalpha, serves as the "glue" which tethers ERalpha to SHC binding sites on the activated IFG-1 receptors. Use of siRNA methodology to knock down SHC allows the conclusion that SHC is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1 and reduces the activation of MAP kinase. We have shown that this drug is a potent inhibitor of mTOR and this provides the major means for inhibition of cell proliferation. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy ofaromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
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PMID:Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells. 1863 82

The spatial organization of K-Ras proteins into nanoclusters on the plasma membrane is essential for high-fidelity signal transduction. The mechanism underlying K-Ras nanoclustering is unknown. We show here that K-Ras.GTP recruits Galectin-3 (Gal-3) from the cytosol to the plasma membrane where it becomes an integral nanocluster component. Importantly, we show that the cytosolic level of Gal-3 determines the magnitude of K-Ras.GTP nanoclustering and signal output. The beta-sheet layers of the Gal-3 carbohydrate recognition domain contain a hydrophobic pocket that may accommodate the farnesyl group of K-Ras. V125A substitution within this hydrophobic pocket yields a dominant negative Gal-3(V125A) mutant that inhibits K-Ras activity. Gal-3(V125A) interaction with K-Ras.GTP reduces K-Ras.GTP nanocluster formation, which abrogates signal output from the Raf/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) pathway. Gal-3(V125A) negatively regulates cell growth and reduces cellular transformation. Thus, regulation of K-Ras nanocluster formation and signal output by Gal-3 critically depends on the integrity of the Gal-3 hydrophobic pocket. These results show that Gal-3 overexpression in breast cancer cells, which increases K-Ras signal output, represents oncogenic subversion of plasma membrane nanostructure.
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PMID:K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3. 1870 84

Indole-3-carbinol (I3C), a phytochemical derived from cruciferous vegetables such as broccoli and Brussels sprouts, has potent antiproliferative effects in human breast cancer cells and has been shown to decrease metastatic spread of tumors in experimental animals. Using chemotaxis and fluorescent-bead cell motility assays, we demonstrated that I3C significantly decreased the in vitro migration of MDA-MB-231 cells, a highly invasive breast cancer cell line. Immunofluorescence staining of the actin cytoskeleton revealed that concurrent with the loss of cell motility, I3C treatment significantly increased stress fiber formation. Furthermore, I3C induced the localization of the focal adhesion component vinculin and tyrosine-phosphorylated proteins to the cell periphery, which implicates an indole-dependent enhancement of focal adhesions within the outer boundary of the cells. Coimmunoprecipitation analysis of focal adhesion kinase demonstrated that I3C stimulated the dynamic formation of the focal adhesion protein complex without altering the total level of individual focal adhesion proteins. The RhoA-Rho kinase pathway is involved in stress fiber and focal adhesion formation, and I3C treatment stimulated Rho kinase enzymatic activity and cofilin phosphorylation, which is a downstream target of Rho kinase signaling, but did not increase the level of active GTP-bound RhoA. Exposure of MDA-MB-231 cells to the Rho kinase inhibitor Y-27632, or expression of dominant negative RhoA ablated the I3C induced formation of stress fibers and of peripheral focal adhesions. Expression of constitutively active RhoA mimicked the I3C effects on both processes. Taken together, our data demonstrate that I3C induces stress fibers and peripheral focal adhesions in a Rho kinase-dependent manner that leads to an inhibition of motility in human breast cancer cells.
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PMID:Indole-3-carbinol inhibits MDA-MB-231 breast cancer cell motility and induces stress fibers and focal adhesion formation by activation of Rho kinase activity. 1917 91

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