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)

Recent advances in defining the molecular mechanisms of cell cycle control in eukaryotes provide a basis for better understanding the hormonal control of cell proliferation in normal and neoplastic breast epithelium. It is now clear that a number of critical steps in cell cycle progression are controlled by families of serine/threonine kinases, the cdks. These kinases are activated by interactions with various cyclin gene products which form the regulatory subunits of the kinase complexes. Several families of cyclins control cell cycle progression in G1 phase, cyclins C, D and E, or in S, G2 and mitosis, cyclins A and B. Recent studies have defined the expression and regulation of cyclin genes in normal breast epithelial cells and in breast cancer cell lines. Following growth arrest of T-47D breast cancer cells by serum deprivation restimulation with insulin results in sequential induction of cyclin genes. Cyclin D1 mRNA increases within 1 h of mitogenic stimulation and is followed by increased expression of cyclins D3 and E in G1 phase, cyclin A in late G1/early S phase and cyclin B1 in G2. Similar results were observed following epidermal growth factor stimulation of normal breast epithelial cells. Other hormones--oestrogens and progestins--and growth factors--insulin-like growth factor-I and basic fibroblast growth factor--with actions in G1 were also investigated for their effects on G1 cyclin gene expression. In all cases there was an excellent correlation between the induction of cyclin D1 mRNA and subsequent entry into S phase. Furthermore, growth inhibition by antioestrogens and concurrent G1 arrest were preceded by an acute decrease in cyclin D1 gene expression. These observations suggest a likely role for cyclin D1 in mediating many of the known hormonal effects on cell proliferation in breast epithelial cells.
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PMID:Cyclin gene expression and growth control in normal and neoplastic human breast epithelium. 827 47

The human p27kip1 gene encodes a cyclin-dependent kinase inhibitor implicated in the negative regulation of the cell cycle. In order to elucidate the possible role of p27 mutations in the development or progression of human breast cancer, we have studied the occurrence of genetic abnormalities in this gene in a series of 30 primary breast carcinomas. Direct sequence analysis of the polymerase chain reaction amplified human p27 gene revealed the occurrence of two sequence variations with respect to the reported sequence; both variants were also present in the lymphocyte DNA from the same patients. First, a silent G to A change at codon 142 (Thr) was detected in a single case. Second, a T to G transversion at codon 109, resulting in a Val to Gly change, was observed in eight tumour DNA samples (26%) and in 31 out of 80 unrelated normal individuals (39%). This latter change creates a Bg/I restriction site that might be useful for genetic analysis of human tumours. Despite the occurrence of these polymorphisms, we did not however find any evidence of somatic mutations in the coding region of the p27 gene. On the basis of these results, we suggest that alterations in the integrity of the human p27 gene are not common events in human breast carcinomas.
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PMID:Mutational analysis of the human cyclin-dependent kinase inhibitor p27kip1 in primary breast carcinomas. 855 69

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

In eukaryotes, phosphorylation of serine, threonine, and tyrosine residues on proteins is a fundamental posttranslational regulatory process for such functions as signal transduction, gene transcription, RNA splicing, cellular adhesion, apoptosis, and cell cycle control. Based on functional groups present in natural product serine/threonine protein phosphatase (PSTPase) inhibitors, we have designed pharmacophore model 1 and demonstrated the feasibility of a combinatorial chemistry approach for the preparation of functional analogues of 1. Preliminary biological testing of 18 structural variants of 1 has identified two compounds with growth inhibitory activity against cultured human breast cancer cells. In vitro inhibition of the PSTPase PP2A was demonstrated with compound 1d. Using flow cytometry we observed that compound f1 caused prominent inhibition in the G1 phase of the cell cycle. Thus, the combinatorial modifications of the minimal pharmacophore 1 can generate biologically interesting antiproliterative agents.
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PMID:Combinatorial synthesis and biological evaluation of library of small-molecule Ser/Thr-protein phosphatase inhibitors. 904 68

We have recently demonstrated that both antibodies to Gal alpha(1,3)Gal, and the Gal alpha(1,3)Gal binding lectin (IB4), bind a synthetic peptide (DAHWESWL), there being a similar recognition of carbohydrate and peptide structures. We now report that the anti-Gal alpha(1,3)Gal antibodies and IB4 lectin also react with peptides encoded by mucin genes (MUC 1, 3, 4)-sequences known to be rich in serine, threonine and proline. This activity was demonstrated (1) by the ability of mucin derived peptides to block the reaction of anti-Gal alpha(1,3)Gal antibodies and IB4 lectin with a Gal alpha(1,3)Gal+ pig endothelial cell line; the reactions were specific and did not occur with a random peptide containing the same sequences or with other mucin peptides; (2) by the fact that anti-mucin1 antibodies could react with the Gal alpha(1,3)Gal expressed after transfection of COS cells (Gal alpha(1,3)Gal-,Muc1-) with cDNA encoding the pig alpha, 3galactosyltransferase; and (3) that the IB4 lectin and anti-Gal alpha(1,3)Gal antibodies could react with mucin 1 found on the surface of human breast cancer cells. Thus natural occurring anti-Gal alpha(1,3)Gal antibodies found in all human serum can react with self (Muc1) peptides expressed in large amounts on the surface of tumour cells but not on normal cells. The findings are of interest and serve to explain the previously reported findings that human cells can, at times, express Gal alpha(1,3)Gal; such expression is an artefact, the reaction is due to the phenomenon described herein, i.e. that anti-Gal alpha(1,3)Gal antibodies react with mucin peptides.
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PMID:Natural human anti-Gal alpha(1,3)Gal antibodies react with human mucin peptides. 907 19

PLK (polo-like kinase) belongs to a family of serine/threonine kinases and represents the human counterpart of polo in Drosophila melanogaster and of CDC5 in Saccharomyces cerevisiae. It is strongly involved in spindle formation and chromosome segregation during mitosis. We have shown previously that PLK mRNA expression correlates with the mitotic activity of cells and the prognosis of lung cancer patients. In this report, the level of PLK protein was analyzed using immunohistochemical techniques. PLK protein was found expressed in the nuclei of tumor cells from lung and breast cancer as well as in several tumor cell lines. Furthermore, in peripheral lymphocytes treated with phytohemagglutinin, elevated proliferative activity of the cells correlated with the up-regulation of PLK protein expression. In contrast, in U937 and HL-60 cells after induction of differentiation with phorbol ester, PLK immunostaining disappeared under conditions of terminal differentiation. Most of the PLK protein was found in the nucleus of proliferating cells with diffuse but distinct staining also in the cytoplasm. Taken together, high levels of PLK protein are associated with cellular proliferation. Combined with other proliferative and oncogene markers, PLK may be useful for improved prediction of the clinical prognosis of cancer patients and for early cancer diagnosis. Due to its activity late in the cell cycle, it may be a target for cancer chemotherapy.
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PMID:Polo-like kinase, a novel marker for cellular proliferation. 909 72

Estrogens induce cell proliferation in target tissues by stimulating progression through G1 phase of the cell cycle, but the underlying molecular targets remain undefined. To determine the role of the cyclin/cyclin-dependent kinase (CDK)/retinoblastoma protein (pRB) pathway in this response we treated MCF-7 breast cancer cells with the pure estrogen antagonist ICI 182780 to inhibit estrogen-induced gene expression and induce G1 phase arrest. Subsequent treatment with 17beta-estradiol resulted in the synchronous entry of cells into S phase commencing at 12 h. The proportion of cells in S phase reached a maximum of 60% at 21-24 h. Cells subsequently completed mitosis and entered a second semisynchronous round of replication. Entry into S phase was preceded by increased activity of both Cdk4 and cyclin E-Cdk2 and hyperphosphorylation of pRB, all within the first 3-6 h of estradiol treatment. The increase in Cdk4 activity was accompanied by increases in cyclin D1 mRNA and protein, indicating that an initiating event in the activation of Cdk4 was increased cyclin D1 gene expression. In contrast, the levels of Cdk2 and the CDK inhibitors p21 (WAF1/CIP1/SDI1) and p27 (KIP1) in total cell lysates and in cyclin E immunoprecipitates were unaltered at these early time points. However, an inhibitory activity was present in antiestrogen-pretreated cell lysates toward recombinant cyclin E-Cdk2 and was relieved by estradiol treatment. This activity was attributable predominantly to p21. These apparently conflicting data were resolved by performing gel filtration chromatography, which revealed that only a minority of cyclin E-Cdk2 complexes were active following estradiol treatment. Active complexes eluted at a higher molecular weight than inactive complexes, were relatively deficient in both p21 and p27, and contained Cdk2 with increased threonine 160 phosphorylation, consistent with a mechanism of activation of cyclin E-Cdk2 involving both reduced CDK inhibitor association and CDK-activating kinase-mediated phosphorylation of Cdk2. These results provide an explanation for the early activation of both cyclin D1-Cdk4 and cyclin E-Cdk2 complexes that accompany G1-S phase progression in response to estradiol.
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PMID:Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. 909 45

Rhenium-188 (beta- = 2.2 MeV; gamma = 155 keV; T1/2 16.9 hours) is an attractive therapeutic radioisotope which is produced from decay of the reactor-produced tungsten-188 parent (T1/2 69 days) and thus conveniently obtained on demand by elution from the alumina-based tungsten-188 /rhenium-188 generator system. The rhenium-188 is obtained as sodium perrhenate by elution of the generator with 0.9% saline. The post elution use of disposable tandem, ion-exchange columns is a simple method for the concentration of rhenium-188 saline solutions with specific volumes > 500 mCi/ml. This method can also extend the useful shelf-life of the generator, which can be as long as one year. The long useful shelf-life of the generator is expected to provide rhenium-188 at very reasonable costs for routine preparation of a variety of radiopharmaceuticals for the treatment of a variety of cancers including breast cancer. We are evaluating two types of Re-188-labeled agents under investigation which have potential for the treatment of breast cancer. Rhenium-188-labeled hydroxyethylidenediphosphonate (HEDP) and Re-188-dimercaptosuccinic acid (DMSA) are being applied for palliative treatment of pain associated with skeletal metastases, and the Re-188-RC-160 somatostatin analogue [cyclic NH2-(D)-Phe-Cys-Try-(D)-Trp-Lys-Val-Cys-Trp-NH2] for somatostatin-receptor-positive tumors. The results of initial clinical studies with the two bone pain agents demonstrate good targeting to skeletal metastases, and use of Re-188-HEDP has resulted in pain palliation with minimal bone marrow suppression in the initial patient studies. While these initial studies have been conducted in patients with prostate cancer, similar results are expected in planned studies in breast cancer patients. In animal studies, Re-188-RC-160 has been successfully used for the local/regional treatment of experimental breast cancer and other cancers. Re-188-RC-160 binds to somatostatin-receptor-positive cells both in vitro and in vivo, including breast cancer cells (ZR-75-1 breast carcinoma and NCI-H69 human small cell ling carcinoma), but not to binding-negative cells (Raji, Burkitt's lymphoma). A structurally similar Re-188-cyclic peptide with different binding specificity (CTOP [cyclic NH2-(D)-Phe-Cys-Try-(D)-Trp-Orn-Thr-Pen-Thr-ol]; an opiate-receptor antagonist) did not bind to target cells. Both gentisic acid and ascorbic acid are present in the Re-188-HEDP and Re-188-RC-160 formulations, and have been found to also significantly reduce radiolytic degradation of the somatostatin peptide analogues, and may have general application in the stabilization of Re-188-labeled radio-pharmaceuticals.
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PMID:Availability of rhenium-188 from the alumina-based tungsten-188/rhenium-188 generator for preparation of rhenium-188-labeled radiopharmaceuticals for cancer treatment. 917 35

Treatment of MCF-7 breast cancer cells with 50 nM okadaic acid triggers an apoptotic response which is accompanied by a 7-fold increase in the activity of a protein kinase with a relative molecular mass of 53 kDa. The activity of the kinase was stimulated by cell treatment with inhibitors of phosphoprotein phosphatase 1 and 2A, but not by stressing conditions. Okadaic acid-induced stimulation of the 53 kDa protein kinase was not abolished by coincubation of cells with cycloheximide. We conclude that stimulation of the 53 kDa protein kinase by inhibitors of phosphoprotein phosphatases involves pre-existing molecular components whose activity depends on the phosphorylation state of serine/threonine residues.
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PMID:Inhibitors of phosphoprotein phosphatases 1 and 2A cause activation of a 53 kDa protein kinase accompanying the apoptotic response of breast cancer cells. 923 60

Genetically based differences in carcinogen metabolism have been related to polymorphisms of the cytochrome P450IA1 gene (CYPIA1) and the null genotypes of glutathione S-transferase classes mu and theta (GSTM1 and GSTT1). By PCR we examined the genotypes of CYPIA1, GSTM1, and GSTT1 in relation to breast cancer risk in Caucasian and African-American women. The study included 164 Caucasian and 59 African-American women with primary invasive breast cancer and age-matched female controls. Enzyme polymorphisms included in this study were the null deletions of GSTM1 and GSTT1 and the m1 (MspI), m2 (codon 462: isoleucine-->valine), m3 (MspI-AA), and m4 (codon 461: threonine-->asparagine) polymorphisms of CYPIA1. Contrary to previous reports by other investigators, none of the enzyme genotypes, individually or combined, appear to associate with an increased risk for breast cancer in Caucasian or African-American women. We also report that the recently described m4 allele occurs at a lower frequency in African-Americans than Caucasians and is not linked with breast cancer in either race. Thus, it is unlikely that polymorphisms of GSTM1, GSTT1, or CYPIA1 represent susceptibility factors for breast cancer in Caucasians or African-Americans.
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PMID:Breast cancer and CYPIA1, GSTM1, and GSTT1 polymorphisms: evidence of a lack of association in Caucasians and African Americans. 942 59


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