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)

The antiestrogen tamoxifen has been used successfully in the treatment of breast cancer. In an attempt to elucidate its mode of action, its effects on steroid hormone receptor concentration and RNA polymerase activities in the uteri of ovariectomized rats have been compared with those of estradiol. A single dose of estradiol and tamoxifen, separately or in combination, produced slight increases in uterine wet weight 12 h after injection. Whereas both estradiol and tamoxifen could promote translocation of the estrogen receptor, only estradiol caused cytoplasmic replenishment of the receptor. Both compounds, separately and in combination, stimulated the production of cytoplasmic progesterone receptor 12 h after treatment. Estradiol produced and maintained significant elevations in RNA polymerase I activity, whereas the effects on this enzyme brought about by taxoxifen were less and transitory. However, estrogen and antiestrogen caused equal increases in RNA polymerase II activity, but, again, the effects of taxoxifen were shortlived when compared to those brought about by estradiol. Stimulation of RNA polymerase II activity was due to the availability of increased numbers of apparent initiation sites. These results point to a basic inefficacy in the antiestrogen-receptor complex; although it is able to promote early tissue responses characteristic of an estrogen, these cannot be sufficiently maintained.
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PMID:Effects of estradiol and the antiestrogen tamoxifen on steroid hormone receptor concentration and nuclear ribonucleic acid polymerase activities in rat uteri. 49 77

To investigate the effect of ligand (be it hormone, antihormone, or no hormone) on the interaction between estrogen receptor (ER) and chromatin, we have used formaldehyde as a cross-linking agent in intact MCF-7 human breast cancer cells. After a 1- to 2-h hormone treatment, the cells are exposed for 8 min to formaldehyde, which is added directly to their culture medium to minimize environmental perturbation. Nuclei are prepared from formaldehyde-treated cells and their contents are fractionated on CsCl density gradients to separate DNA-protein complexes from free protein. Peak gradient fractions are assayed for the presence of specific proteins by immunoblot of sodium dodecyl sulfate-polyacrylamide gel patterns. Using this approach, we find that 0.15% formaldehyde is optimal for cross-linking ER to chromatin. We detect ER and the large subunit of RNA polymerase II with DNA from formaldehyde-treated, but not from untreated cells. On the other hand, actin (a cytoplasmic protein) and small nuclear ribonucleoprotein particle proteins (nuclear RNA binding proteins) are not cross-linked to DNA. Therefore, cross-linking appears to be selective and fractionation is efficient. Interestingly, we detect similar levels of ER (as well as RNA polymerase II) with DNA from formaldehyde-treated cells, regardless of whether the cells are preexposed to estrogen (17 beta-estradiol at 10(-8) M), antiestrogen (ICI 164,384 at 10(-7) or 10(-6) M), or no hormone. These results, using covalent cross-linking in intact cells, indicate that both ligand-occupied and unoccupied ER are associated with chromatin.
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PMID:Cross-linking of estrogen receptor to chromatin in intact MCF-7 human breast cancer cells: optimization and effect of ligand. 228 Jul 70

DNA-protein interactions around the regulatory region of the pS2 gene were studied to gain insight into the mechanisms that operate in the estrogen receptor regulated expression of this gene in the MCF-7 human breast cancer cell. Using a revised photocrosslinking technology in combination with gel retardation assays, two distinct multiprotein DNA complexes were shown to assemble in an estrogen receptor-dependent process. Immunological analysis demonstrated the participation of both the estrogen receptor and a c-fos related protein in the formation of these complexes. The results support a model of estrogen receptor function in which the receptor facilitates the formation of multiprotein complexes at DNA sites that can regulate the transcription of a hormone responsive gene by RNA polymerase II and any additional general transcription machinery. These receptor-containing complexes are referred to as "receptorsomes."
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PMID:Estrogen receptor-dependent formation of two distinct multiprotein complexes on the human pS2 gene regulatory segment. Participation of a c-fos related protein. 825 52

Estrogen receptors (ER) are ligand-inducible transcription factors regulated by Ser(Thr)-O-phosphorylation. Many transcription factors and eukaryotic RNA polymerase II itself are also dynamically modified by Ser(Thr)-O-linked N-acetylglucosamine moieties (O-GlcNAc). Here we report that subpopulations of murine, bovine, and human estrogen receptors are modified by O-GlcNAc. O-GlcNAc moieties were detected on insect cell-expressed, mouse ER (mER) by probing with bovine milk galactosyltransferase, followed by structural analysis. Wheat germ agglutinin-Sepharose affinity chromatography also readily detected terminal GlcNAc residues on subpopulations of ER purified from calf uterus, from human breast cancer cells (MCF-7), or from mER produced by in vitro translation. These data suggest that greater than 10% of these populations of estrogen receptors bear O-GlcNAc. Site mapping of insect cell expressed mER localized one major site of O-GlcNAc addition to Thr-575, within a PEST region of the carboxyl-terminal F domain. Based upon their relative resistance to both hexosaminidase and to in vitro galactosylation, O-GlcNAc moieties appear to be largely buried on native mER. This dynamic saccharide modification, like phosphorylation, may play a role in modulating the dimerization, stability, or transactivation functions of estrogen receptors.
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PMID:A subpopulation of estrogen receptors are modified by O-linked N-acetylglucosamine. 899 54

The RNA polymerase II (Pol II) holoenzyme in yeast is an essential transcriptional regulatory complex which has been defined by genetic and biochemical approaches. The mammalian counterpart to this complex, however, is less well defined. Experiments herein demonstrate that, along with Pol II and SRB proteins, proteins associated with transcriptional regulation as cofactors are associated with the Pol II holoenzyme. Earlier experiments have demonstrated that the breast cancer-associated tumor suppressor BRCA1 and the CREB binding protein (CBP) were associated with the holoenzyme complex. The protein related to CBP, the E1A-associated p300 protein, is shown in these experiments to be associated with the holoenzyme complex as well as the BRG1 subunit of the chromatin remodeling SWI/SNF complex. Importantly, the Pol II holoenzyme complex does not contain some factors previously reported as stoichiometric components of the holoenzyme complex, most notably the proteins which function in repair of damaged DNA, such as PCNA, RFC and RPA. The presence of the p300 coactivator and the chromatin-modifying BRG1 protein support a role for the Pol II holoenzyme as a key target for regulation by enhancer binding proteins.
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PMID:Factors associated with the mammalian RNA polymerase II holoenzyme. 944 79

The tumor suppressor gene BRCA1, is a nuclear phosphoprotein which associates with RNA polymerase II holoenzyme. CBP is a component of the holoenzyme. Previously, we have characterized two new BRCA1 splice variants BRCA1a/p110 and BRCA1b/p100. In the present study, the carboxy-terminal domain of transcription factor CBP interacts both in vivo and in vitro with full length BRCA1a and BRCA1b proteins as demonstrated by mammalian two- hybrid assays, co-immunoprecipitation/western blot studies, GST binding assays and histone acetyl transferase (HAT) assays of BRCA1 immunoprecipitates from human breast cancer cells. Our results suggest that one of the mechanisms by which BRCA1 proteins function is through recruitment of CBP associated HAT/FAT (transcription factor acetyl-transferase) activity for acetylation of either themselves or general transcription factors or both to specific promoters resulting in transcriptional activation.
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PMID:BRCA1 splice variants BRCA1a and BRCA1b associate with CBP co-activator. 953 57

The breast cancer specific tumour suppressor protein, BRCA1 (refs 1,2), activates transcription when linked with a DNA-binding domain and is a component of the RNA polymerase II (Pol II) holoenzyme. We show here that RNA helicase A (RHA) protein links BRCA1 to the holoenzyme complex. The region of BRCA1 which interacts with RHA and, thus, the holoenzyme complex, corresponds to subregions of the BRCT domain of BRCA1 (ref. 9). This interaction was shown to occur in yeast nuclei, and expression in human cells of a truncated RHA molecule which retains binding to BRCA1 inhibited transcriptional activation mediated by the BRCA1 carboxy terminus. These data are the first to identify a specific protein interaction with the BRCA1 C-terminal domain and are consistent with the model that BRCA1 functions as a transcriptional coactivator.
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PMID:BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. 966 97

About half of the familial breast cancer cases are found to bear mutations in the breast cancer susceptibility gene 1 (BRCA1). The majority of BRCA1 mutations produce a truncated protein and BRCA1-associated breast tumors exhibit a number of defined tumor phenotypes. The function of BRCA1 has been examined in gene knockout mice in which the nullizygous mice die early in utero, but this lethality can be partially rescued by a nullizygous p53 mutation. Wild-type BRCA1 protein binds to a number of cellular proteins, including DNA repair protein Rad51, tumor suppressor p53, RNA polymerase II holoenzyme, RNA helicase A, CtBP-interacting protein, c-myc, BRCA1-associated RING domain protein (BARD1), BRCA2 protein, etc. These proteins likely mediate the involvement of BRCA1 in DNA repair, transcriptional transactivation, and cell cycle control. Overall, BRCA1 protein may act as a converging vehicle for cell regulatory proteins to associate with. Therefore, mutations in BRCA1 may affect the composition of these complexes on which dysregulation of cellular functions with eventual development of malignancy is expected.
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PMID:The functions of breast cancer susceptibility gene 1 (BRCA1) product and its associated proteins. 1019 18

1alpha,25-dihydroxyvitamin D(3) (VD) is a pleiotropic nuclear hormone that also has effects on cell cycle regulation. VD and its synthetic analogues are known inhibitors of cellular growth and inducers of apoptosis, however, the primary mediator genes of these effects largely remain unknown. In order to identify novel targets for VD, that may be involved in the regulation of the cell cycle, a differential display PCR (ddPCR) approach was applied to the MCF-7 human breast cancer cell line, which provided the gene for cyclin C as an interesting candidate. Quantitative assessment of cyclin C expression showed that the gene was significantly upregulated by VD and its analogues, EB1089 and CB1093 both on the level of mRNA expression and more so on the level of protein expression in MCF-7 cells. Upregulation of cyclin C protein expression could also be confirmed in MeWo human melanoma and in U937 human promyelocytic leukemia cells. This observation adds a new gene candidate to the list of primary VD responding genes. Cyclin C is not a typical cyclin, as it apparently modulates the activity of the RNA polymerase II complex, which provides fresh insight into the mechanisms of cell cycle and general transcriptional regulation by VD and its analogues.
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PMID:Cyclin C is a primary 1alpha,25-dihydroxyvitamin D(3) responding gene. 1067 18

Mutations in the BRCA1 and BRCA2 genes predispose women to familial, early-onset breast cancer. Both the BRCA1 and BRCA2 proteins appear to function in the homologous recombination pathway of DNA double-strand break repair. Both BRCA1 and BRCA2 have also been implicated in transcription by RNA polymerase II, for both proteins have domains which, when tethered adjacent to a promoter, can activate transcription. In experiments reported here, we have used protein affinity chromatography and coimmunoprecipitation techniques to show that the putative N-terminal acidic transcriptional activation domain of BRCA2 interacts with replication protein A (RPA), a protein essential for DNA repair, replication and recombination. This interaction was not mediated by DNA and was specific for human RPA but not yeast RPA. Since the cancer-predisposing mutation Y42C in BRCA2 significantly compromised the interaction between RPA and BRCA2, this interaction may be biologically important. That BRCA2 protein in HeLa cell extract also coimmunoprecipitated with RPA suggested that this interaction occurs in vivo. Therefore, the transcriptional activation domains within BRCA2, and perhaps BRCA1, may provide links to RPA and DNA repair processes rather than transcription.
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PMID:Interaction between BRCA2 and replication protein A is compromised by a cancer-predisposing mutation in BRCA2. 1252 4


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