Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibiting protein prenylation is an attractive means to modulate cellular processes controlled by a variety of signaling proteins, including oncogenic proteins such as Ras and Rho GTPases. The largest class of prenylated proteins contain a so-called CaaX motif at their carboxyl termini and are subject to a maturation process initiated by the attachment of an isoprenoid lipid by either protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I (GGTase-I). Inhibitors of FTase, termed FTIs, have been the subject of intensive development in the past decade and have shown efficacy in clinical trials. Although GGTase-I inhibitors (GGTIs) have received less attention, accumulating evidence suggests GGTIs may augment therapies using FTIs and could be useful to treat a myriad of additional disease states. Here we describe the characterization of a selective, highly potent, and cell-active GGTase-I inhibitor, GGTI-DU40. Kinetic analysis revealed that inhibition by GGTI-DU40 is competitive with the protein substrate and uncompetitive with the isoprenoid substrate; the Ki for the inhibition is 0.8 nM. GGTI-DU40 is highly selective for GGTase-I both in vitro and in living cells. Studies indicate GGTI-DU40 blocks prenylation of a number of geranylgeranylated CaaX proteins. Treatment of MDA-MB-231 breast cancer cells with GGTI-DU40 inhibited thrombin-induced cell rounding via a process that involves inhibition of Rho proteins without significantly effecting parallel mobilization of calcium via Gbetagamma. These studies establish GGTI-DU40 as a prime tool for interrogating biologies associated with protein geranylgeranylation and define a novel structure for this emerging class of experimental therapeutics.
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PMID:A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity, and cellular activity. 1651 96

Akt1 is frequently up-regulated in human tumors and has been shown to accelerate cell proliferation and to suppress programmed cell death; consequently, inhibition of the activity of Akt1 has been seen as an attractive target for therapeutic intervention. Paradoxically, hyperactivation of the Akt1 oncogene can also prevent the invasive behavior that underlies progression to metastasis. Here we show that overexpression of activated myr-Akt1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation, leading to reduced Rho-GTPase activity, decreased actin stress fibers and focal adhesions, and reduced motility and invasion. Overexpression of TSC2 rescues the migration phenotype of myr-Akt1-expressing tumor cells, and high levels of TSC2 in breast cancer patients correlate with increased metastasis and reduced survival. These data indicate that the functional properties of genes designated as oncogenes or tumor suppressor genes depend on the context of the cell type and the tissues studied, and suggest the need for caution in designing therapies targeting the function of individual genes in epithelial tissues.
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PMID:Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. 1653 97

The expression of podoplanin, a small mucin-like protein, is upregulated in the invasive front of a number of human carcinomas. We have investigated podoplanin function in cultured human breast cancer cells, in a mouse model of pancreatic beta cell carcinogenesis, and in human cancer biopsies. Our results indicate that podoplanin promotes tumor cell invasion in vitro and in vivo. Notably, the expression and subcellular localization of epithelial markers are unaltered, and mesenchymal markers are not induced in invasive podoplanin-expressing tumor cells. Rather, podoplanin induces collective cell migration by filopodia formation via the downregulation of the activities of small Rho family GTPases. In conclusion, podoplanin induces an alternative pathway of tumor cell invasion in the absence of epithelial-mesenchymal transition (EMT).
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PMID:Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. 1661 32

D4-GDI is a Rho GDP dissociation inhibitor that is widely expressed in hematopoietic cells. Its possible expression and function in breast cancer cells has not been described. Here, we found that D4-GDI is expressed in a panel of breast cancer cell lines, but not in benign-derived mammary epithelial cells. Knockdown of D4-GDI expression in MDA-MB-231 cells by RNA interference blocks cell motility and invasion. The cells lacking D4-GDI grown on Matrigel revert to a normal breast epithelial phenotype characterized by the formation of cavitary structures. Silencing D4-GDI expression inhibits beta1-integrin expression and cell-matrix adhesion. Reintroduction of D4-GDI fully restored both beta1-integrin expression and cellular invasion. Knockdown of D4-GDI in BT549 cells results in a similar effect. These results show that D4-GDI modulates breast cancer cell invasive activities.
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PMID:D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. 1674 Jun 94

Rho family GTPases are frequently overexpressed in breast cancers, which regulate cancer cell migration and invasion. They require prenylation, a lipid post-translational modification, for full biological functions. We examined the effects of 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (fluvastatin), a selective farnesyltransferase inhibitor (FTI-277) and a selective geranylgeranyltransferase type I inhibitor (GGTI-298) on in vitro invasive capacity of MDA-MB-231 human breast cancer cells into the endothelial cell monolayer in a transendothelial migration assay. Although, at a maximal dose of 5 microM, fluvastatin did not affect the integrity of endothelial cell monolayer, the transendothelial migration of MDA-MB-231 cells was inhibited potently by fluvastatin in a dose-dependent manner. The transendothelial migration of MDA-MB-231 cells was also inhibited potently by GGTI-298 in a dose-dependent manner but weakly by FTI-277. The inhibitory effects of fluvastatin, GGTI-298 and FTI-277 on MDA-MB-231 cell invasion were shown to correlate well with inhibition of the membrane localization of RhoA and RhoC, but not with Ras. These results suggest that geranylgeranylation step of RhoA and RhoC could be a good therapeutic target for the prevention of invasion and metastasis of breast cancer cells.
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PMID:Inhibition of transendothelial migration and invasion of human breast cancer cells by preventing geranylgeranylation of Rho. 1677 3

Axin, a negative regulator of the Wnt signaling pathway, contains a canonical regulator of G protein signaling (RGS) core domain. Herein, we demonstrate both in vitro and in cells that this domain interacts with the alpha subunit of the heterotrimeric G protein G12 but not with the closely related Galpha13 or with several other heterotrimeric G proteins. Axin preferentially binds the activated form of Galpha12, a behavior consistent with other RGS proteins. However, unlike other RGS proteins, that of axin (axinRGS) does not affect intrinsic GTP hydrolysis by Galpha12. Despite its inability to act as a GTPase-activating protein, we demonstrate that in cells, axinRGS can compete for Galpha12 binding with the RGS domain of p115RhoGEF, a known G12-interacting protein that links G12 signaling to activation of the small G protein Rho. Moreover, ectopic expression of axinRGS specifically inhibits Galpha12-directed activation of the Rho pathway in MDA-MB 231 breast cancer cells. These findings establish that the RGS domain of axin is able to directly interact with the alpha subunit of heterotrimeric G protein G12 and provide a unique tool to interdict Galpha12-mediated signaling processes.
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PMID:The regulator of G protein signaling domain of axin selectively interacts with Galpha12 but not Galpha13. 1686 83

The ability of cancer cells to undergo invasion and migration is a prerequisite for tumor metastasis. Rho, a Ras-related small GTPase, and the Rho-associated coiled coil-containing protein kinases (Rho kinases, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. Inhibitors of this pathway have been shown to inhibit tumor cell motility and metastasis. Here, we show that fasudil [1-(5-isoquinolinesulfonyl)-homopiperazine], an orally available inhibitor of Rho kinases, and its metabolite 1-(hydroxy-5-isoquinoline sulfonyl-homopiperazine) (fasudil-OH) modify tumor cell morphology and inhibit tumor cell migration and anchorage-independent growth. In addition, we show that fasudil inhibited tumor progression in three independent animal models. In the MM1 peritoneal dissemination model, tumor burden and ascites production were reduced by > 50% (P < 0.05). In the HT1080 experimental lung metastasis model, fasudil decreased lung nodules by approximately 40% (P < 0.05). In the orthotopic breast cancer model with MDA-MB-231, there were 3-fold more tumor-free mice in the fasudil-treated group versus saline control group (P < 0.01). Fasudil has been approved for the treatment of cerebral vasospasm and associated cerebral ischemic symptoms. In patients, fasudil is well tolerated without any serious adverse reactions. Therefore, the concept of Rho kinase inhibition as an antimetastatic therapy for cancer can now be clinically explored.
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PMID:The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models. 1698 48

Overexpression of RhoA in cancer indicates a poor prognosis, because of increased tumor cell proliferation and invasion and tumor angiogenesis. We showed previously that anti-RhoA small interfering RNA (siRNA) inhibited aggressive breast cancer more effectively than conventional blockers of Rho-mediated signaling pathways. This study reports the efficacy and lack of toxicity of intravenously administered encapsulated anti-RhoA siRNA in chitosan-coated polyisohexylcyanoacrylate (PIHCA) nanoparticles in xenografted aggressive breast cancers (MDA-MB-231). The siRNA was administered every 3 days at a dose of 150 or 1500 microg/kg body weight in nude mice. This treatment inhibited the growth of tumors by 90% in the 150-microg group and by even more in the 1500-microg group. Necrotic areas were observed in tumors from animals treated with anti-RhoA siRNA at 1500 microg/kg, resulting from angiogenesis inhibition. In addition, this therapy was found to be devoid of toxic effects, as evidenced by similarities between control and treated animals for the following parameters: body weight gain; biochemical markers of hepatic, renal, and pancreatic function; and macroscopic appearance of organs after 30 days of treatment. Because of its efficacy and the absence of toxicity, it is suggested that this strategy of anti-RhoA siRNA holds significant promise for the treatment of aggressive cancers.
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PMID:Intravenous delivery of anti-RhoA small interfering RNA loaded in nanoparticles of chitosan in mice: safety and efficacy in xenografted aggressive breast cancer. 1700 68

FVB/N mice transgenic for nontransforming rat neu develop spontaneous breast cancers that are neu positive and estrogen receptor negative, mimicking premenopausal human breast cancer. These animals have been widely used as a model for immunobased therapies targeting HER-2/neu. In this study, we used serological analysis of recombinant cDNA expression libraries to characterize the antigenic repertoire of neu transgenic (neu-tg) mice and questioned the ability of this murine model to predict potential human tumor antigens. After screening 3 x 10(6) clones from 3 different cDNA libraries, 15 tumor antigens were identified, including cytokeratin 2-8, glutamyl-prolyl-tRNA synthetase, complement C3, galectin 8, and serine/threonine-rich protein kinase 1. Multiple proteins involved in the Rho/Rho-associated, coiled coil-containing protein kinase (Rock) signal transduction pathway were found to be immunogenic, including Rock1, Rho/Rac guanine nucleotide exchange factor 2, and schistosoma mansoni adult worm antigen preparation 70. All of the identified antigens are self-proteins that are expressed in normal tissues in addition to breast tumors and the majority of the antigens are intracellular proteins. More than half of the mouse tumor antigens have human homologues that have been reported previously as tumor antigens. Finally, the tumor-specific antibody immunity and marked immune cell infiltration that was observed in mice with spontaneous tumors were not observed in mice with transplanted tumors. Our results indicate that neu-tg mice bearing spontaneous tumors develop humoral immunity to their tumors similar to cancer patients and that tumor antigens identified in transgenic mouse may predict immunogenic human homologues.
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PMID:The tumor antigen repertoire identified in tumor-bearing neu transgenic mice predicts human tumor antigens. 1701 35

High-dose busulfan is an important component in many conditioning protocols for hematopoietic stem cell or bone marrow transplantation. Treatment with busulfan results in the inhibition of cell cycle progression and apoptosis of tumor cells. As Rho GTPases are involved in cell cycle regulation, we investigated the influence of modified Rho guanine nucleotide dissociation inhibitor-alpha (GDI), a physiological inhibitor of Rho GTPases, on busulfan activity in cancer cells. RhoGDIalpha has been shown to be overexpressed in multiple types of tumors such as ovarian and breast cancer. To investigate the role of RhoGDIalpha, we established a RhoGDIalpha knockdown by the transient transfection of HEK293 cells with specific small interfering RNA resulting in strongly reduced RhoGDIalpha mRNA and protein expression. Other members of the RhoGDI family such as RhoGDIbeta and RhoGDIgamma were not affected. In RhoGDIalpha knockdown cells, cell cycle regulation was not altered by the downregulation of RhoGDIalpha; however, the rate of apoptotic cells increased when compared with the control small interfering RNA-transfected cells. In addition, treatment of cells with busulfan resulted in a further increased apoptotic rate, as determined by fluorescence-activated cell sorter analysis and caspase-3 activation. Such a sensitization of RhoGDIalpha small interfering RNA transfected cells was also found upon treatment with doxorubicin and taxol. In summary, we could demonstrate that the expression of RhoGDIalpha influences the sensitivity of cells toward busulfan-induced cytotoxicity.
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PMID:Reduced expression of Rho guanine nucleotide dissociation inhibitor-alpha modulates the cytotoxic effect of busulfan in HEK293 cells. 1726 67


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