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 effect of increased intracellular cAMP on MCF-7 breast cancer cell growth was examined by treating cells with either forskolin, an activator of adenylate cyclase, or 8-[4-chlorophenylthio]-cAMP (8-CPT-cAMP), a cAMP analog. Compared to cells maintained in control medium, treatment with either 1 or 10 microM forskolin decreased cell growth by 17% and 68%, respectively, whereas treatment with 250 microM 8-CPT-cAMP decreased cell growth by 29%. To determine whether this effect of cAMP on cell growth was mediated by inhibition of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1 and -2), two mitogen-activated protein kinases, the effect of cAMP on growth factor-induced ERK activity in MCF-7 cells was examined. Treatment with either insulin-like growth factor I (IGF-I) or epidermal growth factor (EGF) for 10 min stimulated a 4- to 8-fold increase in ERK1 and -2 activity. This effect of IGF-I and EGF was not inhibited by increased intracellular cAMP generated by pretreatment of the cells with 10 microM forskolin. Similarly, 10 microM forskolin had no effect on IGF-I- or EGF-induced ERK activity in cells treated with growth factor for 30 min. To determine whether cAMP inhibits other growth factor-mediated effects, its effect on the activity of the serum response element (SRE), a DNA promoter element whose activity is regulated by a variety of growth-promoting events, was examined. For these assays, MCF-7 cells were transiently transfected with pTK81-SRE-Luc, a luciferase fusion gene that contains the SRE cloned 5' to a minimal thymidine kinase promoter and the luciferase gene. Treatment with either IGF-I or EGF increased pTK81-SRE-Luc activity in a dose-dependent fashion. Pretreatment of cells with 10 microM forskolin decreased IGF-I- and EGF-stimulated luciferase activity by approximately 75%. An intermediate effect was observed using 1 microM forskolin. When intracellular cAMP levels were increased using 8-CPT-cAMP, similar results were obtained. SRE activity is dependent upon the activation by phosphorylation of a ternary complex factor; included among the ternary complex factors is Elk-1. When MCF-7 cells were cotransfected with a vector that expresses a Gal4/Elk-1 fusion protein and UAS-TK-Luc, a plasmid that contains two Gal4 DNA recognition sites cloned 5' to a thymidine kinase promoter and the luciferase gene, treatment with forskolin partially inhibited the activation of Elk-1 by IGF-I and EGF. These data demonstrate that in MCF-7 breast cancer cells, cAMP has no effect on IGF-I- or EGF-induced ERK activity, but it inhibits growth factor-induced transcription. Taken together with the effects of cAMP on IGF-I- and EGF-induced Elk-1 activation, these data suggest that the effect of cAMP on SRE activity occurs distal to ERK activation, possibly via inhibition of an ERK-independent pathway. Finally, these data indicate that the effect of increased intracellular cAMP on breast cancer growth may be mediated through inhibition of specific growth factor-induced effects, including gene transcription.
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PMID:Growth factor-induced transcription via the serum response element is inhibited by cyclic adenosine 3',5'-monophosphate in MCF-7 breast cancer cells. 916 3

To investigate the functional differences between estrogen receptor (ER) alpha and beta subtypes, we studied the expression and the transcription stimulating activities of these receptors. RT-PCR has demonstrated that ER alpha is expressed at a high level in MCF-7 cells derived from human breast cancer. Both ER alpha and ER beta were expressed at a lower level in HOS-TE85 and Saos2 cells derived from human osteosarcoma. Chloramphenicol acetyltransferase reporter assay detected the transcriptional activation by the endogenous receptor only in MCF-7 cells. Agonistic effect of tamoxifen was observed as strong as that of 17beta-estradiol on ERE activation in MCF-7 cells at the concentration of 10(-7) M when ERE-containing reporter is constructed with beta-globin promoter. The effect of tamoxifen was not apparent when the reporter was constructed with thymidine kinase promoter, suggesting that the differential gene activation between tamoxifen and estrogen may take place depending upon ERE-promoter context. Agonistic activity of tamoxifen was also detected in COS-7 and Saos-2 cells, but not in HEC-1 cells derived from human endometrial carcinoma via exogenously expressed ER. Interestingly, this effect was ER alpha specific. Thus, we demonstrate that agonistic effect of tamoxifen depends on the cell type, ERE-promoter context, and ER subtype. These parameters would explain at least a part of the tissue specific effects of antiestrogens in vivo.
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PMID:Agonistic effect of tamoxifen is dependent on cell type, ERE-promoter context, and estrogen receptor subtype: functional difference between estrogen receptors alpha and beta. 922 41

To investigate the potential of the thymidine kinase gene from Varicella zoster virus (VZVtk) to act as a suicide gene, VZVtk was transferred via a dicistronic retroviral construct into MCF7, T-47D and MDA-MB-435 human breast cancer cells. The cytotoxicity of antiviral drugs was then evaluated in vitro on the wild-type and transduced cells. Acyclovir and ganciclovir did not show any selective toxicity for the modified cells. In contrast, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was extremely toxic for the VZVtk expressing cells, with IC50 values of 0.6 microM, 0.1 microM and 0.06 microM for MCF7, T-47D and MDA-MB-435 cells, respectively. The selectivity index of BVDU (ie the IC50 value ratio of the wild-type to the VZVtk cells) was 400 for MCF7, 750 for T-47D and 2000 for MDA-MB-435 cells. To test the system in vivo, VZVtk carrying MDA-MB-435 cells were inoculated subcutaneously into nude mice. An intraperitoneal treatment with BVDU administered at the emergence of the tumors, led to a prolonged arrest of the tumor growth and a reduced tumor mass. This effect was BVDU dose-dependent. No bystander effect of BVDU killing could be demonstrated in vitro on mixed populations of VZVtk positive and negative MDA-MB-435 cells. However, an important bystander effect was observed in identical experiments performed on 9L rat gliosarcoma cells infected with the VZVtk-carrying vector. These results demonstrate the efficiency of VZVtk as a suicide gene when BVDU is used as prodrug. The bystander effect measured in vitro, depends however on the tumoral cell type used.
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PMID:Potential of Varicella zoster virus thymidine kinase as a suicide gene in breast cancer cells. 923 Oct 72

Retinyl methyl ether (RME) is known to prevent the development of mammary cancer. However, the mechanism by which RME exerts its anticancer effect is presently unclear. The diverse biological functions of retinoids, the vitamin A derivatives, are mainly mediated by their nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARs and RXRs are ligand-dependent transcriptional factors that either activate gene transcription through their binding to retinoic acid response elements or repress transactivation of genes containing the activator protein 1 (AP-1) binding site. Previous studies demonstrated that RME can modulate transcriptional activity of retinoid receptors on retinoic acid response elements, suggesting that regulation of retinoid receptor activity may mediate the anticancer effect of RME. In this study, we present evidence that RME can down-regulate AP-1 activity induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, insulin, growth factors, and the nuclear proto-oncogenes c-Jun and c-Fos. Transient transfection assays demonstrate that inhibition of AP-1 activity occurs on the human collagenase promoter containing an AP-1 binding site or the thymidine kinase promoter linked with an AP-1 binding site. In HeLa cells, the inhibition is observed when RAR-alpha and/or RXR-alpha but not RAR-beta or RAR-gamma expression vectors are cotransfected, whereas the endogenous retinoid receptors in breast cancer cells T-47D and ZR-75-1 were sufficient to confer the inhibition by RME. Furthermore, using gel retardation assay, we show that 12-O-tetradecanoylphorbol-13-acetate- and epidermal growth factor-induced AP-1 binding activity in breast cancer cells is inhibited by RME. These results suggest that one of the mechanisms by which RME prevents cancer development may be due to the repression of AP-1-responsive genes.
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PMID:Retinyl methyl ether down-regulates activator protein 1 transcriptional activation in breast cancer cells. 927 11

In a previous study (Cancer Res 54: 5860-5866, 1994), we observed irreversible inactivation of a chimeric estrogenic response induced by the antiestrogen 4-hydroxytamoxifen. This rapidly occurring effect (t1/2= 7 days) was not a consequence of a cell selection process, nor of a loss of estrogen receptor functionality, but was a direct antiestrogen effect occurring on every cell at the transcriptional level. In the present study, we analyzed the detailed methylation status of the chimeric gene, and investigated the gene for the presence of mutations. The inactivation process was found to be strictly correlated with a modification at a methylation-sensitive restriction site Not I borne by the integrated gene. As the gene promoter contains part of the Herpes simplex virus promoter for thymidine kinase. which is a CpG-rich promoter, we investigated the CpGs located in this part of the promoter by genomic sequencing procedures. None of these CpGs were methylated, suggesting that the inactivation process was not driven by particular modifications of this foreign part of the promoter. Furthermore, no mutations were found in the entire gene promoter of inactivated cells. In conclusion, the present study highlighted a connection between the rapid silencing of an estrogenic response induced by 4-hydroxytamoxifen, and a localized epigenetic modification of the corresponding gene. No genotoxicity of 4-hydroxytamoxifen was observed. Similar epigenetic modifications might also occur for natural genes, and lead to the acquisition of a new cell phenotype.
Breast Cancer Res Treat 1998 Jan
PMID:Rapid tamoxifen-induced inactivation of an estrogenic response is accompanied by a localized epigenetic modification but not by mutations. 949 78

Reconstitution of the p53-dependent apoptotic pathway by gene transfer of a recombinant wild-type p53 minigene leads to rapid apoptotic cell death in breast and other cancer cell types expressing null or mutant p53. Tumour cells expressing wild-type p53 have been reported to be more resistant to this treatment strategy, presumably as a result of mutations in downstream regulators of p53-dependent apoptotic signalling. The MCF-7 breast cancer cell line is representative of this class of tumour cell. Our recent observation of a p53-dependent apoptotic response following adenovirus-mediated HSV thymidine kinase gene transfer and gancyclovir treatment led us to reexamine recombinant p53 cytotoxicity in MCF-7 cells. Infection with a recombinant adenovirus expressing wild-type p53 resulted in a dramatic increase in p53 protein levels and was accompanied by an increase in p21WAF/CIP1 protein levels and G1 arrest within 24 hours post-infection. A significant decrease in MCF-7 cell viability was first observed at 5 days post-infection and coincided with the appearance of morphological and biochemical changes consistent with apoptotic cell death. By day 7 post-treatment, cell viability decreased to 45% and clonogenic survival was reduced to 12% of controls. The results demonstrate that persistent, high level expression of recombinant p53 can induce programmed cell death in MCF-7 cells. While the mechanism by which p53 overexpression overcomes the defect in downstream apoptotic signalling is not clear, our data suggests that this treatment strategy may be beneficial for the class of tumour cells represented by the MCF-7 cell line.
Breast Cancer Res Treat 1998 Apr
PMID:Therapeutic potential of recombinant p53 overexpression in breast cancer cells expressing endogenous wild-type p53. 959 74

Pulmonary metastases are the main cause of death of patients with several types of cancer, including osteosarcoma, renal cell carcinoma, malignant melanoma, and breast cancer. Previously, we demonstrated that intralesional injection of the recombinant adenovirus (Ad) vector containing the herpes simplex virus thymidine kinase (TK) gene driven by an osteocalcin (OC) promoter (Ad-OC-TK) effectively suppressed the growth of osteosarcoma cells in vitro and tumors in vivo in a tumor-specific manner when supplemented with the prodrug acyclovir (ACV). In this communication, we studied the potential efficacy of the treatment of osteosarcoma pulmonary metastases with a systemic delivery route of Ad-OC-TK supplemented with ACV. We established osteosarcoma lung metastases in nude mice by the intravenous injection of rat osteosarcoma cells, ROS 17/2.8. These cells colonized and formed tumor nodules within 1 week in the lungs of nude mice. Whereas systemic delivery of a recombinant Ad vector containing the Escherichia coli beta-galactosidase (beta-gal) gene driven by a Rous sarcoma virus universal promoter (Ad-RSV-beta-gal) resulted in the nonspecific expression of beta-gal activity in the lung parenchyma, Ad-OC-beta-gal administration resulted in specific beta-gal expression in tumor cells deposited in the lung. When nude mice bearing ROS 17/2.8 lung tumors were treated with systemic Ad-OC-TK through tail vein administration, subsequent intraperitoneal ACV treatment significantly decreased the number of tumor nodules (P < .0001) and the net lung wet weight (P = .0005) while significantly increasing (.005 < P < .01) the survival of animals, when compared with untreated and Ad-OC-TK- or ACV-treated control groups. These results suggest that Ad-OC-TK/ACV may be used as a systemic therapy for the treatment of osteosarcoma lung metastasis.
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PMID:In vivo suppression of osteosarcoma pulmonary metastasis with intravenous osteocalcin promoter-based toxic gene therapy. 982 46

The development of resistance to radiation and chemotherapeutic agents that cause DNA damage is a major problem for the treatment of breast and other cancers. The p53 tumor suppressor gene plays a direct role in the signaling of cell cycle arrest and apoptosis in response to DNA damage, and p53 gene mutations have been correlated with increased resistance to DNA-damaging agents. Herpes simplex virus thymidine kinase (HSV-tk) gene transfer followed by ganciclovir (GCV) treatment is a novel tumor ablation strategy that has shown good success in a variety of experimental tumor models. However, GCV cytotoxicity is believed to be mediated by DNA damage-induced apoptosis, and the relationship between p53 gene status, p53-mediated apoptosis, and the sensitivity of human tumors to HSV-tk/GCV treatment has not been firmly established. To address this issue, we compared the therapeutic efficacy of adenovirus-mediated HSV-tk gene transfer and GCV treatment in two human breast cancer cell lines: MCF-7 cells, which express wild-type p53, and MDA-MB-468 cells, which express high levels of a mutant p53 (273 Arg-His). Treating MCF-7 cells with AdHSV-tk/GCV led to the predicted increase in endogenous p53 and p21WAF1/CIP1 protein levels, and apoptosis was observed in a significant proportion of the target cell population. However, treating MDA-MB-468 cells under the same conditions resulted in a much stronger apoptotic response in the absence of induction in p21WAF1/CIP1 protein levels. This latter result suggested that HSV-tk/GCV treatment can activate a strong p53-independent apoptotic response in tumor cells that lack functional p53. To confirm this observation, four additional human breast cancer cell lines expressing mutant p53 were examined. Although a significant degree of variability in GCV chemosensitivity was observed in these cell lines, all displayed a greater reduction in cell viability than MCF-7 or normal mammary cells treated under the same conditions. These results suggest that endogenous p53 status does not correlate with chemosensitivity to HSV-tk/GCV treatment. Furthermore, evidence for a p53-independent apoptotic response serves to extend the potential of this therapeutic strategy to tumors that express mutant p53 and that may have developed resistance to conventional genotoxic agents.
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PMID:Differential chemosensitivity of breast cancer cells to ganciclovir treatment following adenovirus-mediated herpes simplex virus thymidine kinase gene transfer. 1019 85

Estrogens are important for bone homeostasis and are classified as antiresorptive agents. One of the mechanisms for this effect is the inhibition of cytokine-induced bone resorption, which is mediated in part through an interaction between the estrogen receptor (ER) and nuclear factor (NF)-kappaB in osteoblasts. We present evidence that bone-resorbing cytokines that activate NF-kappaB conversely inhibit ligand-dependent ER activity in the conditionally immortalized human osteoblast cell line, HOB-03-CE6. Treatment of HOB-03-CE6 cells with 17beta-estradiol (17beta-E2) up-regulated reporter gene activity [ERE-thymidine kinase (tk)-luciferase] 3- to 5-fold in a dose-dependent manner (EC50 = 1.0 pM). However, cotreatment of the cells with 17beta-E2 and increasing concentrations of either tumor necrosis factor-alpha (TNF alpha), interleukin-1alpha (IL-1alpha), or IL-1beta completely suppressed ERE-tk-luciferase activity in a dose-dependent manner (IC50 = 0.05-5.0 pM). On the other hand, treatment of the cells with growth factors either up-regulated or had no effect on ERE-tk-luciferase expression. Neither TNF alpha, IL-1alpha, nor IL-1beta treatment affected basal reporter gene activity in the cells, and the TNF alpha effect was reversed by a neutralizing antibody to the cytokine. TNF alpha treatment also suppressed ligand-dependent ER activity in MCF-7 human breast cancer cells, but not in Chinese hamster ovary cells that overexpressed human ER alpha, even though both cell lines responded to the cytokine as measured by the up-regulation of NFkappaB-tk-luciferase activity. TNF alpha treatment did not affect the steady state levels of either ER alpha or ER beta messenger RNA expression by the HOB-03-CE6 cells, nor did it reduce [125I]17beta-E2 binding. Moreover, TNF alpha treatment only weakly inhibited ligand-dependent glucocorticoid receptor activity in the HOB-03-CE6 cells. Bone-resorbing cytokines, which do not signal through the NF-kappaB pathway, did not suppress ERE-tk-luciferase activity in HOB-03-CE6 cells. Treatment of the cells with 17beta-E2 partially suppressed the activation of NF-kappaB by TNF alpha, but did not block cytokine-induced IL-6 secretion. Finally, cotreatment of HOB-03-CE6 cells with an antisense oligonucleotide to NF-kappaB p50 partially reversed the suppression of ERE-tk-luciferase activity by TNF alpha. In summary, these data provide evidence for a potent feedback inhibition of estrogen action in human osteoblasts that is at least partly mediated by the activation of NF-kappaB.
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PMID:Suppression of ligand-dependent estrogen receptor activity by bone-resorbing cytokines in human osteoblasts. 1034 28

We have synthesized and studied the ability of a series of nine novel 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] analogs to inhibit clonal growth of myeloid leukemic cells (HL,60), prostate (LNCaP, PC-3 and DU-145) and breast (MCF-7) cancers cells. DU-145 cells were actively resistant to compounds (cmpd) with all of these modifications, but when we removed C-19 (E, 1,25-Dihydroxy-23E-ene-26,27-hexafluoro-19-nor-20-cyclopropy l- cholecalciferol) an analog resulted that was inhibitory against all three prostate cell lines, breast and HL-60 cell lines. Further analysis showed that pulse exposure (3 days, 10(-7) M) to this analog was enough to inhibit clonal growth of PC-3 cell by 50%. Furthermore, cmpd E increased the number of PC-3 cells in G1 and decreased the number in S phase. 1,25(OH)2D3 mediates its biological activities through specific binding to the vitamin D3 receptor (VDR) and subsequent association with vitamin D3 response elements (VDRE) in genes modulated by 1,25(OH)2D3. Several novel vitamin D3 cmpds have recently been identified which have 5- to 1000-fold greater abilities to induce differentiation and to inhibit proliferation of prostate cancer, breast cancer and HL-60 leukemic blast cells as compared to the parental 1,25(OH)2D3. To clarify the mechanism by which nine of these vitamin D3 analogs mediate their remarkably potent biological activities, we have investigated their abilities in PC-3 prostate cancer cells to transactivate a chroramphenicol acetyl transferase (CAT) reporter gene containing a VDRE from the human osteocalcin gene attached to a thymidine kinase minimal promoter. Dose-response studies of Cmpd E showed that in serumless culture conditions, transactivation of the VDRE-CAT was stronger than cmpd J [1,25(OH)2D3]. Then, we investigated the effects of vitamin D3 cmpd J in mice. Our data showed the growth inhibitory action of the vitamin D3 cmpd E in prostate cancer cell line (PC-3) was stastically superior to the non-treatment group in terms of tumor size and tumor weight in mice. In summary, this is the first report of a potent series of 20-cyclopropyl-cholecalciferol vitamin D3 analogs with the ability to inhibit proliferation of LNCaP, PC-3, DU-145, MCF-7 and HL-60 cell lines. These cmpds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.
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PMID:20-Cyclopropyl-cholecalciferol vitamin D3 analogs: a unique class of potent inhibitors of proliferation of human prostate, breast and myeloid leukemia cell lines. 1047 Jan 2


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