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)

The c-erbB-2 proto-oncogene encodes a receptor tyrosine kinase (RTK) closely related to the epidermal growth factor receptor (EGFR). Overexpression of erbB-2 occurs in approximately 20% of human breast tumours, where increased expression correlates with poor patient prognosis. The EGFR is coupled to the Ras signalling pathway by interaction with the adaptor protein Grb2, and Sos, a Ras GDP-GTP exchange factor. In this study, activation of the erbB-2 receptor and its association with Grb2 and Sos was investigated in breast cancer cell lines which overexpress erbB-2. The receptor was found to be tyrosine phosphorylated in all cell lines in which it is overexpressed. Western blotting of Grb2 and Sos immuneprecipitates from such cells revealed co-precipitation of erbB-2, demonstrating association of the Grb2/Sos complex with erbB-2 in vivo. Furthermore, a fusion protein containing only the SH2 domain of Grb2 bound to erbB-2 immobilized on nitrocellulose, indicating that association with Grb2 is direct and mediated by the SH2 domain of Grb2. The degree of association between the erbB-2 receptor and Grb2 in vivo was related to erbB-2 overexpression, and MAP kinase, which functions downstream from Ras, displayed markedly increased activity in cell lines overexpressing erbB-2. These results demonstrate that erbB-2 is coupled to Ras signalling via the Grb2/Sos complex, and that overexpression of this receptor in breast cancer cells leads to amplification of the Ras signalling pathway.
 ...
PMID:Activation of the Ras signalling pathway in human breast cancer cells overexpressing erbB-2. 797 Jul 20

Little is known regarding the regulation of expression of the RHOA protooncogene, a member of the family of genes encoding Ras-related GTP-binding proteins. We have previously reported that the 3' untranslated region (UTR) of RHOA was contained within a genomic sequence which flanked the 5' end of the human glutathione peroxidase 1-encoding gene [J.A. Moscow et al., J. Biol. Chem. 267 (1992) 5949-5958]. Our previous studies revealed the presence of multiple (1.8 and 1.5 kb) RHOA mRNA species in breast cancer cell lines and of three putative polyadenylation signals in the RHOA 3' UTR. In this report, we have isolated several RHOA cDNAs from a multidrug-resistant MCF-7 human breast cancer cell line. Sequence analyses of these RHOA cDNA clones indicate that multiple polyadenylation signals are used to terminate RHOA transcripts. RNase-protection analysis demonstrated that all three polyadenylation signals are utilized in breast cancer cell lines and RNA stability studies demonstrated that RHOA RNA species with different 3' ends have equivalent stability. Since little is known about the RNA expression of RHOA in human tumors, and since both activated and non-activated RHOA genes possess transformation potential, we analyzed RHOA mRNA in lung and colon tumors by Northern blot and RNase-protection analyses. In all eight lung tumors examined, RHOA RNA levels were decreased relative to the level in normal surrounding tissue, whereas RHOA expression was decreased in only two of six colon tumors. We also found that lovastatin-induced cell cycle arrest resulted in increased RHOA RNA expression in breast cancer cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Utilization of multiple polyadenylation signals in the human RHOA protooncogene. 803 7

A receptor blotting technique was used to detect SH2 domain containing epidermal growth factor receptor (EGFR) substrates that exhibited differential expression either between normal breast epithelial cells and breast cancer cells or between different human breast cancer cell lines. This identified a 25 kD protein, subsequently identified as Grb2, which was markedly overexpressed in three breast cancer cell lines (MCF-7, MDA-MB-361 and -453) relative to both normal breast epithelial cells and the majority of breast cancer cell lines. Northern blot analysis revealed that 7/19 breast cancer cell lines exhibited more than twofold overexpression of Grb2 mRNA, with overexpression correlating with high expression of erbB receptors. In MCF-7, MDA-MB-361 and -453 cells the overexpression of Grb2 mRNA and protein was accompanied by a small amplification of the Grb2 gene locus. Overexpression of Grb2 correlated with increased complex formation between Grb2 and the hSos-1 Ras GDP-GTP exchange protein. This upregulation of the Ras signalling pathway might modulate the growth factor sensitivity of human breast cancer cells and therefore play a role in tumour progression.
 ...
PMID:Overexpression of the Grb2 gene in human breast cancer cell lines. 805 37

CD44s (standard form of CD44) is a transmembrane glycoprotein whose external domain displays extracellular matrix adhesion properties by binding both hyaluronic acid (HA) and collagen. The cytoplasmic domain of CD44s interacts with the cytoskeleton by binding directly to ankyrin. It has been shown that post-translational modifications, such as phosphorylation (by protein kinase C), acylation (by acyl-transferase) and GTP-binding enhanced CD44's interaction with cytoskeletal proteins. Most importantly, the interaction between CD44s and the cytoskeletal protein, ankyrin, is required for the modulation of CD44s cell surface expression and its adhesion function. Recently, a number of tumor cells and tissues have been shown to express CD44 variant (CD44v) isoforms. Using RT-PCR and DNA sequence analyses, we have found that unique CD44 splice variant isoforms are expressed in both prostate and breast cancer cell lines and carcinomas. Most importantly intracellular ankyrin is preferentially accumulated underneath the patched/capped structures of CD44 variant isoform in both breast and prostate cancer cells attached to HA-coated plates. We propose that selective expression of CD44v isoforms unique for certain metastatic carcinomas and their interaction with the cytoskeleton may play a pivotal role in regulating tumor cell behavior during tumor development and metastasis.
 ...
PMID:Involvement of CD44 and its variant isoforms in membrane-cytoskeleton interaction, cell adhesion and tumor metastasis. 875 Jan 86

Raf-1 protein serine/threonine kinase has been implicated in growth and damage-responsive signal transduction pathways. Several reports indicate an important role of Ras protein in the growth factor-induced activation of Raf-1. Here we investigated the possible involvement of Ras in ionizing radiation-induced activation of Raf-1. Irradiation of MDA-MB 231 human breast cancer cells caused an increase in GTP-binding and hydrolysis on Ras, and co-immunoprecipitations of endogenous Grb2 with Sos and Raf-1 with Ras. An increase in the level of membrane-bound Raf-1, and tyrosine-phosphorylation of Raf-1 were observed after irradiation. Consistent with these changes, irradiation of cells stimulated the catalytic activity of Raf-1. Finally, radiation treatment of breast cancer cells led to an increase in the phosphorylation and activity of the mitogen-activated protein kinase. Based on these biochemical modifications in vivo, we conclude that Raf-1 functions as an effector of Ras in the radiation-responsive signal transduction pathway leading to the activities of Raf-1 and mitogen-activated protein kinase.
 ...
PMID:Association of Grb2 with Sos and Ras with Raf-1 upon gamma irradiation of breast cancer cells. 923 77

Prolactin (PRL) is recognized as a growth and differentiating hormone in the human breast. These effects are mediated by the PRL receptor (PRLr); when stimulated the PRL-PRLr complex activates several signaling cascades, including those involving the GTP-binding proteins Ras and Rac. The activation of these signaling pathways has been associated with cytoskeletal alterations and increased cellular motility. We hypothesized that such changes could occur in PRL-stimulated human breast cancer cells. To test this hypothesis, complementary studies, including wound closure, time-lapse video microscopy (TLVM), and Boyden chamber assay were performed. These studies revealed that PRL significantly enhanced the migration of the breast cancer cell lines T47D, MCF7, and MDA23 1. Co-stimulation with PRL was noted to potentiate epidermal growth factor (EGF)-induced cell motility. IF microscopy of filamentous actin using rhodamine-conjugated phalloidin revealed a significant and rapid generation of both membrane ruffling and stress fibers in response to PRL, an effect inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. In sum, these data reveal that PRL stimulation modulates the cytoskeleton and induces the motility of human breast cancer cells in vitro, events that have been associated with the progression of mammary carcinoma in vivo. Given the recently delineated autocrine-paracrine role for PRL in human breast cancer, these findings could be of appreciable clinical significance.
 ...
PMID:Prolactin as a chemoattractant for human breast carcinoma. 1053 79

TC21 is a Ras-like GTPase with high oncogenic potential that is found mutated in some human tumors and overexpressed in breast cancer cell lines. We have conducted cellular and biochemical studies in order to understand the role of this protein in signal transduction and to unveil the signaling elements that participate in the TC21 pathway. Using gene transfer experiments, we demonstrate here that the TC21 oncogene can induce both cellular transformation in mouse fibroblasts and neuronal-like differentiation in rat PC12 cells. Interestingly, the proto-oncogenic version of TC21 shows also a lower, but significant, activity in both biological processes. We also demonstrate that the similarity of the cellular responses induced by TC21 and Ras derive from the utilization of overlapping pathways. Thus, the exchange of guanosine nucleotides in wild type TC21 is catalyzed by Ras exchange factors. Moreover, TC21 binds physically to c-Raf-1 in a GTP-dependent manner. Finally, overexpression of TC21G23V in NIH3T3 cells results in the activation of c-Raf-1 and the MAPK and the JNK branches of serine/threonine cascades. From these results, we conclude that TC21 promotes Ras-like responses in diverse cell types due to the use of overlapping, if not identical, signaling elements of the Ras oncogenic pathway.
 ...
PMID:Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins. 1055 73

Grb7 is a member of a family of molecular adapters which are able to contribute positively but also negatively to signal transduction and whose precise roles remain obscure. Rnd1 is a member of the Rho family, but, as opposed to usual GTPases, it is constitutively bound to GTP. We show here that Rnd1 and Grb7 interact, in two-hybrid assays, in vitro, and in pull-down experiments performed with SK-BR3, a breast cancer cell line that overexpresses Grb7. This interaction involves switch II loop of Rnd1, a region crucial for guanine nucleotide exchange in all GTPases, and a Grb7 SH2 domain, a region crucial for Grb7 interaction with several activated receptors. The contribution of the interaction between Rnd1 and Grb7 to their respective functions and properties is discussed.
 ...
PMID:Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family. 1066 63

The effects of modifying membrane fatty acid composition on cell growth, phospholipase C (PLC) and protein kinase C (PKC) activities, and prostaglandin E2 (PGE2) secretion were investigated. Hormone responsive MCF-7 human breast cancer cells were incubated in a serum-free medium containing epidermal growth factor and supplemented with physiologic concentrations (0.18-1.78 x 10(-5) M) of linoleic acid (LA) or conjugated linoleic acid (CLA). Linoleic acid stimulated cancer cell growth, while CLA was inhibitory. Supplementation with LA or CLA altered cell membrane composition. Linoleic acid stimulated PLC activity with or without GTP gamma (S), and tended to increase membrane PKC activity. However, CLA supplementation did not modify membrane PLC or PKC activity. Prostaglandin E2 secretion was not influenced by LA or CLA. These data show that growth inhibition by CLA was not mediated through PLC-, PKC- or PGE2-dependent signal transduction pathways, suggesting that another inhibitory mechanism may be involved. Although biological differences appeared to be modest (5-20% of control), the fact that LA and CLA treatment resulted in significant biological effects at physiologic concentrations is relevant, since most human cancers require years to develop.
 ...
PMID:Modulation of MCF-7 breast cancer cell signal transduction by linoleic acid and conjugated linoleic acid in culture. 1081 Mar 38

Although insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 are known to modulate cell growth by reversibly sequestering extracellular insulin-like growth factors, several reports have suggested that IGFBP-3, and possibly also IGFBP-5, have important insulin-like growth factor-independent effects on cell growth. These effects may be related to the putative nuclear actions of IGFBP-3 and IGFBP-5, which we have recently shown are transported to the nuclei of T47D breast cancer cells. We now describe the mechanism for nuclear import of IGFBP-3 and IGFBP-5. In digitonin-permeabilized cells, where the nuclear envelope remained intact, nuclear translocation of wild-type IGFBP-3 appears to occur by a nuclear localization sequence (NLS)-dependent pathway mediated principally by the importin beta nuclear transport factor and requiring both ATP and GTP hydrolysis. Under identical conditions, an NLS mutant form of IGFBP-3, IGFBP-3[(228)KGRKR --> MDGEA], was unable to translocate to the nucleus. In cells where both the plasma membrane and nuclear envelope were permeabilized, wild-type IGFBP-3, but not the mutant form, accumulated in the nucleus, implying that the NLS was also involved in mediating binding to nuclear components. By fusing wild-type and mutant forms of NLS sequences (IGFBP-3 [215-232] and IGFBP-5 [201-218]) to the green fluorescent protein, we identified the critical residues of the NLS necessary and sufficient for nuclear accumulation. Using a Western ligand binding assay, wild-type IGFBP-3 and IGFBP-5, but not an NLS mutant form of IGFBP-3, were shown to be recognized by importin beta and the alpha/beta heterodimer but only poorly by importin alpha. Together these results suggest that the NLSs within the C-terminal domain of IGFBP-3 and IGFBP-5 are required for importin-beta-dependent nuclear uptake and probably also accumulation through mediating binding to nuclear components.
 ...
PMID:Nuclear import of insulin-like growth factor-binding protein-3 and -5 is mediated by the importin beta subunit. 1081 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>