Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

DAL-1 (differentially expressed in adenocarcinoma of the lung)/4.1B is a tumor suppressor gene on human chromosome 18p11.3 whose expression is lost in >50% of primary non-small-cell lung carcinomas. Based on sequence similarity, DAL-1/4.1B has been assigned to the Protein 4.1 superfamily whose members interact with plasma membrane proteins through their N-terminal FERM (4.1/Ezrin/Radixin/Moesin) domain, and cytoskeletal components via their C-terminal SAB (spectrin-actin binding) region. Using the DAL-1/4.1B FERM domain as bait for yeast two-hybrid interaction cloning, we identified protein arginine N-methyltransferase 3 (PRMT3) as a specific DAL-1/4.1B-interacting protein. PRMT3 catalyses the post-translational transfer of methyl groups from S-adenosyl-L-methionine to arginine residues of proteins. Coimmunoprecipitation experiments using lung and breast cancer cell lines confirmed this interaction in mammalian cells in vivo. In vitro binding assays demonstrated that this was an interaction occurring via the C-terminal catalytic core domain of PRMT3. DAL-1/4.1B was determined not to be a substrate for PRMT3-mediated methylation but its presence inhibits the in vitro methylation of a glycine-rich and arginine-rich methyl-accepting protein, GST (glutathione-S-transferase-GAR (glycine- and arginine-rich), which contains 14 'RGG' consensus methylation sites. In addition, induced expression of DAL-1/4.1B in MCF-7 breast cancer cells showed that the DAL-1/4.1B protein significantly inhibits PRMT3 methylation of cellular substrates. These findings suggest that modulation of post-translational methylation may be an important mechanism through which DAL-1/4.1B affects tumor cell growth.
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PMID:DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo. 1533 60

The rodent uterus responds to acute estradiol (E2) treatment with a series of well characterized physiological responses. In a recent screen for genes involved in this response, we found that several genes in the thioredoxin (Txn) pathway were rapidly modified after E2 treatment in the mouse uterus. Txn is a 12-kDa protein with multiple roles in the cell, including protection against oxidative stress and apoptosis, regulation of transcription factor activity, and regulation of cellular proliferation. Txn in combination with Txn reductase (Txnrd) and Txn-interacting protein (Txnip) constitute the mammalian Txn pathway. This pathway exists in multiple locations in the cell, including the cytosol and mitochondria. To analyze the levels of Txn, Txnrd, and Txnip in the uterus, we treated ovariectomized adult mice with a time course of E2 and analyzed mRNA levels by real-time PCR. E2 rapidly decreased the expression of Txnip, but increased the levels of cytosolic Txn1 and Txnrd1 as well as mitochondrial Txn2. Using the ER antagonist, ICI 182,780, and mice lacking functional estrogen receptor alpha (ERalpha), we demonstrate that these E2-mediated changes require ERalpha, but not ERbeta. The repression of Txnip by E2 was also demonstrated in vitro in MCF-7 human breast cancer cells. This repression was blocked by treatment with the histone deacetylase inhibitor, trichostatin A, suggesting that repression by E2 may involve regulation of histone acetylation. We conclude that the rapid E2-mediated activation of the Txn pathway is an important step in the response of the mammalian uterus to estrogen.
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PMID:Estradiol regulates the thioredoxin antioxidant system in the mouse uterus. 1534 72

Vitamin D-interacting protein 205 (DRIP205) is a mediator complex protein that anchors the complex to the estrogen receptor (ER) and other nuclear receptors (NRs). In ZR-75 breast cancer cells treated with 17beta-estradiol (E2) and transfected with a construct containing three tandem estrogen responsive elements (pERE(3)), DRIP205 coactivates ERalpha-mediated transactivation. DRIP205Delta587-636 is a DRIP205 mutant in which both NR boxes within amino acids 587-636 have been deleted and, in parallel transfection studies, DRIP205Delta587-636 also coactivates ERalpha. Moreover, both wild-type and variant DRIP205 also colocalize with ERalpha in the nuclei of transfected cells. Extensive deletion analysis of DRIP205 shows that multiple domains of this protein play a role in coactivation of ERalpha and in interactions with ERalpha. Coactivation of ERalpha by DRIP205 does not require NR boxes, and variants with deletion of N-terminal (amino acids 1-639) and C-terminal (amino acids 576-1566) significantly coactivate ERalpha. DRIP205 resembles p160 coactivators that also interact with multiple regions of ERalpha; however, unlike p160 coactivators, DRIP205 coactivation of ERalpha does not require NR boxes.
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PMID:Vitamin D-interacting protein 205 (DRIP205) coactivation of estrogen receptor alpha (ERalpha) involves multiple domains of both proteins. 1547 64

Adult female rats were ovariectomized and treated with or without estrogen for two weeks. mRNA was obtained from the hypothalamus, uterus, liver, kidney and skeletal muscle and analyzed by Northern blotting and/or RT-PCR. We examined two types of estrogen-responsive genes from rats, neuronal system-related genes (Amphiregulin, AR; Neuropeptide Y-Y1 receptor, NPY-Y1R; Bassoon, BSN; N-Cadherin, N-CADH) and estrogen-susceptible cancer-related genes (C-terminal binding protein interacting protein, CtIP), based on the results of a cDNA microarray analysis which was carried out to profile estrogen-responsive genes in the human breast cancer cell line MCF-7. The N-CADH gene showed identical response to that in MCF-7 cells. In the hypothalamus, all except the AR gene were down-regulated in their expression. In other tissues, the expression showed marked differences: expression of the BSN gene was not detected by either method, and the NPY-Y1R gene showed down-regulation in most tissues except for skeletal muscle. We then analyzed the time course of the estrogen-responsiveness of these genes in several tissues, finding changes in expression patterns especially in skeletal muscle but not in the hypothalamus. Our results show that the estrogen-responsive genes, which were demonstrated simply as either up- or down-regulated in their expression by estrogen in a human cell line using cDNA microarrays, exhibit tissue and temporal-specific expression patterns in adult female rats.
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PMID:Expressional regulation of neuronal and cancer-related genes by estrogen in adult female rats. 1547 35

Mutations in the breast cancer susceptibility gene (BRCA1) account for a significant proportion of hereditary breast and ovarian cancers. Cofactor of BRCA1 (COBRA1) was isolated as a BRCA1-interacting protein and exhibited a similar chromatin reorganizing activity to that of BRCA1. However, the biological role of COBRA1 remains largely unexplored. Here, we report that ectopic expression of COBRA1 inhibited activator protein 1 (AP-1) transcriptional activity in transfected cells in a dose-dependent manner, whereas reduction of endogenous COBRA1 with a small interfering RNA significantly enhanced AP-1-mediated transcriptional activation. COBRA1 physically interacted with the AP-1 family members, c-Jun and c-Fos, and the middle region of COBRA1 bound to c-Fos. Lack of c-Fos binding site in the COBRA1 completely abolished the COBRA1 inhibition of AP-1 trans-activation. These findings suggest that COBRA1 may directly modulate AP-1 pathway and, therefore, may play important roles in cell proliferation, differentiation, apoptosis, and oncogenesis.
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PMID:COBRA1 inhibits AP-1 transcriptional activity in transfected cells. 1553 Apr 30

Vitamin D receptor-interacting protein 150 (DRIP150) has been identified as part of mediator-like complexes that enhance transcriptional activation of the estrogen receptor (ER) and other nuclear receptors (NRs). DRIP150 coactivates ligand-dependent ERalpha-mediated transactivation in ZR-75 and MDA-MB-231 breast cancer cells transfected with a (luciferase) reporter construct (pERE3) regulated by three tandem estrogen-responsive elements. Coactivation of ERalpha by DRIP150 in ZR-75 cells was activation function 2-dependent and required an intact helix 12 that typically interacts with LXXLL motifs (NR box) in p160 steroid receptor coactivators. DRIP150 contains C- and N-terminal NR boxes (amino acids 1182-1186 and 69-73, respectively), and deletion analysis of DRIP150 showed that regions containing these sequences were not necessary for coactivation of ERalpha. Analysis of multiple DRIP150 deletion mutants identified a 23-amino-acid sequence (789-811) required for coactivation activity. Analysis of the protein crystal structure data base identified two regions at amino acids 789-794 and 795-804, which resembled alpha-helical motifs in Lanuginosa lipase/histamine N-methyltransferase and hepatocyte nuclear factor 1, respectively. By using a squelching assay and specific amino acid point mutations within each alpha-helix, the NIFSEVRVYN (795-804) region was identified as the critical sequence required for the activity of DRIP150. These results demonstrate that coactivation of ERalpha by DRIP150 in ZR-75 cells is NR box-independent and requires a novel sequence with putative alpha-helical structure.
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PMID:DRIP150 coactivation of estrogen receptor alpha in ZR-75 breast cancer cells is independent of LXXLL motifs. 1562 66

Breast cancer amplified sequence 2 (BCAS2) was initially identified as a gene that was overexpressed and amplified in some breast cancer cell lines. It was later found to be a component of the spliceosome. Here, we identified BCAS2 as an estrogen receptor (ER) alpha interacting protein by yeast two-hybrid screening. In addition to ER alpha, BCAS2 also interacted with ER beta, TR beta, PR, and PPAR gamma in a ligand-independent way. Transient transfection assays revealed that overexpression of BCAS2 enhanced while inhibition of BCAS2 expression attenuated the estrogen receptor-mediated transcription. BCAS2 potentiated the activation function-2 (AF-2) activity of ER alpha but had no effect on the AF-1 activity. This study suggested that BCAS2 might play an important role in breast cancer development by increasing the estrogen receptor's function.
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PMID:Potentiation of estrogen receptor transcriptional activity by breast cancer amplified sequence 2. 1569 60

The identification of estrogen receptor (ERalpha) target genes is crucial to our understanding of its predominant role in breast cancer. In this study, we used a chromatin immunoprecipitation (ChIP)-cloning strategy to identify ERalpha-regulatory modules and associated target genes in the human breast cancer cell line MCF-7. We isolated 12 transcriptionally active genomic modules that recruit ERalpha and the coactivator steroid receptor coactivator (SRC)-3 to different intensities in vivo. One of the ERalpha-regulatory modules identified is located 3.7 kb downstream of the first transcriptional start site of the RARA locus, which encodes retinoic acid receptor alpha1 (RARalpha1). This module, which includes an estrogen response element (ERE), is conserved between the human and mouse genomes. Direct binding of ERalpha to the ERE was shown using EMSAs, and transient transfections in MCF-7 cells demonstrated that endogenous ERalpha can induce estrogen-dependent transcriptional activation from the module or the ERE linked to a heterologous promoter. Furthermore, ChIP assays showed that the coregulators SRC-1, SRC-3, and receptor-interacting protein 140 are recruited to this intronic module in an estrogen-dependent manner. As expected from previous studies, the transcription factor Sp1 can be detected at the RARA alpha1 promoter by ChIP. However, treatment with estradiol did not influence Sp1 recruitment nor help recruit ERalpha to the promoter. Finally, ablation of the intronic ERE was sufficient to abrogate the up-regulation of RARA alpha1 promoter activity by estradiol. Thus, this study uncovered a mechanism by which ERalpha significantly activates RARalpha1 expression in breast cancer cells and exemplifies the utility of functional genomics strategies in identifying long-distance regulatory modules for nuclear receptors.
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PMID:Functional genomics identifies a mechanism for estrogen activation of the retinoic acid receptor alpha1 gene in breast cancer cells. 1583 16

Breast tumor kinase (Brk) is a member of the Frk family of nonreceptor tyrosine kinases that is overexpressed in a high percentage of human breast tumors. The downstream substrates and effectors of Brk remain largely unidentified. In this study, we carried out immunoprecipitation and mass spectrometry experiments to identify new Brk binding partners. One interacting protein was insulin receptor substrate 4 (IRS-4), a member of the IRS family. We confirmed that Brk associates with IRS-4 in resting and insulin-like growth factor 1 (IGF-1)-stimulated HEK 293 cells. The SH3 and SH2 domains of Brk are both involved in the association. The tyrosine phosphorylation of Brk increases after stimulation with IGF-1, and in MCF-7 breast cancer cells we show that the presence of IRS-4 enhances this effect. Finally, we demonstrate that endogenous Brk and IRS-4 interact in A431 human epidermoid carcinoma cells.
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PMID:Interaction between Brk kinase and insulin receptor substrate-4. 1587 Jun 89

MDR1 is upregulated in many tumors. We have previously detected activation of the MDR1 upstream promoter in metastatic breast cancer cells. MDR1 overlaps with an uncharacterized gene transcribed from the opposite strand, coding for Rap2 interacting protein 9 (RPIP9). Rap2 belongs to the Ras superfamily of GTPases, whose role in breast cancer remains unknown. We developed sensitive methods for detecting and quantifying RPIP9 mRNA and used it to identify these transcripts in normal human tissues, 60 biopsies of primary breast carcinoma, in isolated epithelial cells both from the primary tumor and from associated lymph nodes, and from bone marrow biopsies of 74 breast cancer patients. RPIP9 is expressed at high levels in normal testis, brain and adrenal gland, and at very low levels in normal breast. Tumorigenic breast carcinoma cell lines expressed RPIP9, whereas MCF-10A and HBL-100 that do not form tumors in nude mice had undetectable levels of RPIP9 mRNA. RPIP9 was activated in a high proportion of breast carcinomas (61.6%; n = 60) and a significant correlation with metastatic lymph node invasion (N = 0-3 vs. N > 3, where N = number of lymph nodes invaded; p = 0.031) was found. RPIP9 mRNA could be detected in malignant epithelial cells isolated from the primary tumor and from metastasized lymph nodes as well as in the bone marrow of significantly more poor-prognosis (N > 3) than better-prognosis (N = 0-3) patients (p = 0.001). Therefore, activation of RPIP9 occurs during the malignant breast epithelial transformation and increases with progression toward an invasive phenotype.
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PMID:Expression of RPIP9 (Rap2 interacting protein 9) is activated in breast carcinoma and correlates with a poor prognosis. 1598 26


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