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)

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing para-trifluoromethyl (DIM-C-pPhCF(3)), t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC(6)H(5)) groups are methylene-substituted diindolylmetyhanes (C-DIMs) that activate peroxisome proliferator-activated receptor gamma (PPARgamma) in estrogen receptor alpha-negative MDA-MB-231 and MDA-MB-453 breast cancer cells. C-DIMs inhibit breast cancer cell proliferation; however, inhibition of G(0)/G(1) to S phase progression and cyclin D1 downregulation was observed in MDA-MB-231 but not MDA-MB-453 cells. Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a transforming growth factor beta-like peptide, was also induced by these compounds, and the response was dependent on cell-context dependent activation of kinase pathways. However, inhibition of cell growth, induction of NAG-1 and activation of kinases by C-DIMs were not inhibited by PPARgamma antagonists. Despite the induction of NAG-1 and downregulation of the antiapoptotic protein survivin by C-DIMs in both MDA-MB-231 and MDA-MB-453 cells, apoptotic cell death was not observed. Nevertheless, the cytotoxicity of C-DIMs in vitro was complemented by inhibition of tumor growth in athymic nude mice bearing MDA-MB-231 cells as xenografts and treated with DIM-C-pPhC(6)H(5) (40 mg/kg/day). The growth inhibition of tumors derived from highly aggressive MDA-MB-231 cells suggests a potential role for the C-DIM compounds in the clinical treatment of ER-negative breast cancer.
Breast Cancer Res Treat 2008 May
PMID:1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit proliferation of estrogen receptor-negative breast cancer cells by activation of multiple pathways. 1762 85

Recent investigations have demonstrated that polyphenolic catechins inhibit cancer cell proliferation and tumor growth. However, how the major active component of tea catechins, epigallocatechin-3 gallate (EGCG), mediates anticancerous effects has not been extensively examined. We have investigated the cell growth inhibitory effects of EGCG on cell growth of the human breast cancer cell line MCF-7, and the mechanism of its action with emphasis on the regulation of tumor cell survival. A significant EGCG dose-dependent growth inhibition was observed coordinated with EGCG-induced apoptosis. Analysis of survivin expression after addition of EGCG showed that both survivin mRNA and protein were decreased. The survivin-promoter luciferase activity in EGCG-treated cells was significantly inhibited by 91+/-2.0% (P<0.001), compared with the control. Interestingly, EGCG strongly inhibited the basal activation of phospho-AKT and AKT kinase activity as early as 30 min after treatment. Furthermore, inhibition of AKT kinase activity by EGCG preceded the suppression of survivin (1 h post treatment), followed by increased caspase-9 activity (6 h post treatment). A dominant negative AKT or the phosphatidylinositol 3-kinase inhibitor, LY294002, also strongly inhibited survivin promoter activity, providing further evidence to support the hypothesis that the inhibitory effect of EGCG on survivin is mediated via the AKT pathway. Therefore, EGCG is a potent proapoptotic agent in MCF-7 breast cancer cells that targets survivin expression via suppression of the AKT pathway.
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PMID:Epigallocatechin-3 gallate induces growth inhibition and apoptosis in human breast cancer cells through survivin suppression. 1778

Magnetic nanoparticles (MNP) with a diameter of 8 nm were modified with different generations of polyamidoamine (PAMAM) dendrimers and mixed with antisense survivin oligodeoxynucleotide (asODN). The MNP then formed asODN-dendrimer-MNP composites, which we incubated with human tumor cell lines such as human breast cancer MCF-7, MDA-MB-435, and liver cancer HepG2 and then analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, quantitative reverse transcription-PCR, Western blotting, laser confocal microscopy, and high-resolution transmission electron microscopy. Results showed that the asODN-dendrimer-MNP composites were successfully synthesized, can enter into tumor cells within 15 min, caused marked down-regulation of the survivin gene and protein, and inhibited cell growth in dose- and time-dependent means. No.5 generation of asODN-dendrimer-MNP composites exhibits the highest efficiency for cellular transfection and inhibition. These results show that PAMAM dendrimer-modified MNPs may be a good gene delivery system and have potential applications in cancer therapy and molecular imaging diagnosis.
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PMID:Dendrimer-modified magnetic nanoparticles enhance efficiency of gene delivery system. 1780 28

Breast carcinoma is one of the most common malignant tumors and has become a more common cancer in women. BMP6 was abnormally expressed in breast cancer specimens and cell lines. However, the contribution of BMP6 in promoting breast cancer progression remains unknown. The purpose of our study was to establish whether expression of BMP6 in breast cancer cells affect their proliferation or apoptosis and the mechanism. We found that BMP6 inhibited proliferation of MDA-MB-231 cells and blocked cell cycle at G(0)/G(1) stage. BMP6 also inhibited serum deprivation induced apoptosis in MDA-MB-231 cells. At the 4 days of serum starvation, BMP6 reduced the percentage of caspase-3 positive cells from 49% to 21%, BMP6 also reduced sub-G(1) peak induced by serum starvation. In contrast, BMP6 significantly enhanced survivin expression both at mRNA and protein levels. Dominant negative-survivin and Antisense-survivin impaired BMP6 induced antiapoptotic effect. BMP6 enhanced survivin expression at the transcription level in a Smad-dependent manner. BMP6 also played its antiapoptotic effect through activation p38 MAPK signal pathway, independent of smad/survivin pathway. These results suggested that BMP6 induced cell cycle arrest in estrogen-insensitive breast cancer cells. BMP6 inhibits stress-induced apoptosis via both Smad and p38 signal pathways.
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PMID:Bone morphogenetic protein 6 inhibit stress-induced breast cancer cells apoptosis via both Smad and p38 pathways. 1787 55

The spermine analogue N(1),N(11)-diethylnorspermine (DENSPM) efficiently depletes the polyamine pools in the breast cancer cell line L56Br-C1 and induces apoptotic cell death via the mitochondrial pathway. In this study, we have over-expressed the anti-apoptotic protein Bcl-2 in L56Br-C1 cells and investigated the effect of DENSPM treatment. DENSPM-induced cell death was significantly reduced in Bcl-2 over-expressing cells. Bcl-2 over-expression reduced DENSPM-induced release of the pro-apoptotic proteins AIF, cytochrome c, and Smac/DIABLO from the mitochondria. Bcl-2 over-expression reduced the DENSPM-induced activation of caspase-3. Bcl-2 over-expression also prevented DENSPM-induced Bax cleavage and reduction of Bcl-X(L) and survivin levels. The DENSPM-induced activation of the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase was reduced by Bcl-2 over-expression, partly preventing polyamine depletion. Thus, Bcl-2 over-expression prevented a number of DENSPM-induced apoptotic effects.
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PMID:Novel anti-apoptotic effect of Bcl-2: prevention of polyamine depletion-induced cell death. 1792 Sep 46

Neuronal apoptosis inhibitory protein (NAIP) is a recently identified inhibitor of apoptosis protein. However, the clinical relevance of NAIP expression is not completely understood. In an attempt to determine the clinical relevance of NAIP expression in breast cancer, the levels of NAIP and survivin expression were measured in 117 breast cancer samples and 10 normal breast tissues using quantitative reversetranscriptase-polymerase chain reaction. While there was no evidence of NAIP expression in the normal breast tissue, NAIP was expressed in all breast cancer samples. The level of NAIP expression in breast cancer was significantly higher (257 times) than in the universal tumor control. There was a strong correlation between the level of NAIP expression and the level of survivin expression (p=0.001). The level of NAIP expression in patients with a large tumor (>/=T2) and patients with an unfavorable histology (nuclear grade III) was significantly higher than in those patients with a small tumor (T1) and patients with a favorable histology (nuclear grade I, II) (p=0.026 and p=0.050, respectively). Although the level of NAIP expression was higher in patients with other unfavorable prognostic factors, it was not significant. The three-year relapse-free survival rate was not significantly the patients showing high NAIP expression and patients showing low NAIP expression (86.47plusmn;4.79% vs. 78.74plusmn;6.57%). Further studies should include the expressions of NAIP in a larger number of patients and for a longer period of follow-up to evaluate correlation with metastasis and treatment outcome. In conclusion, NAIP is overexpressed in breast cancer patients with unfavorable clinical features such as stage and tumor size, suggesting that NAIP would play a role in the disease manifestation.
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PMID:Neuronal apoptosis inhibitory protein is overexpressed in patients with unfavorable prognostic factors in breast cancer. 1792 48

Multidrug resistance (MDR) is one of the main reasons for failure of cancer therapy. It may be mediated by overexpression of ATP-dependent efflux pumps or by alterations in survival or apoptotic pathways. Fragments generated by enzymatic degradation of hyaluronan (oHA) were able to modulate growth and cell survival and sensitize MDR breast cancer cells to cytotoxic drugs. In this work the relationship between oHA and MDR in lymphoid malignancies was analyzed using murine lymphoma cell lines resistant to doxorubicin (LBR-D160) or vincristine (LBR-V160) and a sensitive line (LBR-). After oHA treatment, higher apoptosis levels were observed in the resistant cell lines than in the sensitive one. Besides, oHA sensitized LBR-D160 and LBR-V160 to vincristine showing increased apoptosis induction when used in combination with vincristine. Native hyaluronan failed to increase apoptosis levels. As different survival factors could be modulated by hyaluronan, we investigated the PI3K/Akt pathway through PIP3 production and phosphorylated Akt (p-Akt) and survivin expression was also evaluated. Our results showed that oHA decreased p-Akt in the 3 cell lines while anti-CD44 treatment abolished this effect. Besides, survivin was downregulated only in LBR-V160 by oHA. When Pgp function was evaluated, we observed that oHA were able to inhibit Pgp efflux in murine and human resistant cell lines in a CD44-dependent way. In summary, we report for the first time that oHA per se modulate MDR in lymphoma cells by decreasing p-Akt as well as Pgp activity, thus suggesting that oHA could be useful in combination with classical chemotherapy in MDR hematological malignancies.
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PMID:Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating P-glycoprotein activity and PI3K/Akt pathway. 1798 48

There is evidence that specificity proteins (Sp), such as Sp1, Sp3, and Sp4, are overexpressed in tumors and contribute to the proliferative and angiogenic phenotype associated with cancer cells. Sp1, Sp3, and Sp4 are expressed in a panel of estrogen receptor (ER)-positive and ER-negative breast cancer cell lines, and we hypothesized that regulation of their expression may be due to microRNA-27a (miR-27a), which is also expressed in these cell lines and has been reported to regulate the zinc finger ZBTB10 gene, a putative Sp repressor. Transfection of ER-negative MDA-MB-231 breast cancer cells with antisense miR-27a (as-miR-27a) resulted in increased expression of ZBTB10 mRNA and decreased expression of Sp1, Sp3, and Sp4 at the mRNA and protein levels and also decreased activity in cells transfected with constructs containing Sp1 and Sp3 promoter inserts. In addition, these responses were accompanied by decreased expression of Sp-dependent survival and angiogenic genes, including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Moreover, similar results were observed in MDA-MB-231 cells transfected with ZBTB10 expression plasmid. Both as-miR-27a and ZBTB10 overexpression decreased the percentage of MDA-MB-231 cells in S phase of the cell cycle; however, ZBTB10 increased the percentage of cells in G(0)-G(1), whereas as-miR-27a increased the percentage in G(2)-M. This latter response was associated with induction of Myt-1 (another miR-27a target gene), which inhibits G(2)-M through enhanced phosphorylation and inactivation of cdc2. Thus, the oncogenic activity of miR-27a in MDA-MB-231 cells is due, in part, to suppression of ZBTB10 and Myt-1.
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PMID:The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. 1800 46

Dietary phytochemicals exhibit chemopreventive potential in vivo through persistent low-dose exposures, whereas mechanistic in vitro studies with these agents generally use a high-dose single treatment. Because the latter approach is not representative of an in vivo steady state, we investigated antitumor activity of curcumin, 3,3'-diindolylmethane (DIM), epigallocatechin gallate (EGCG), genistein, or indole-3-carbinol (I3C) in breast cancer MDA-MB-231 cells, exposed in long-term culture to low concentrations, achievable in vivo. Curcumin and EGCG increased cell doubling time. Curcumin, EGCG, and I3C inhibited clonogenic growth by 55% to 60% and induced 1.5- to 2-fold higher levels of the basal caspase-3/7 activity. No changes in expression of cell cycle-related proteins or survivin were found; however, I3C reduced epidermal growth factor receptor expression, contributing to apoptosis. Because some phytochemicals are shown to inhibit DNA and histone modification, modulation of expression by the agents in a set of genes (cadherin-11, p21Cip1, urokinase-type plasminogen activator, and interleukin-6) was compared with changes induced by inhibitors of DNA methylation or histone deacetylation. The phytochemicals modified protein and/or RNA expression of these genes, with EGCG eliciting the least and DIM the most changes in gene expression. DIM and curcumin decreased cadherin-11 and increased urokinase-type plasminogen activator levels correlated with increased cell motility. Curcumin, DIM, EGCG, and genistein reduced cell sensitivity to radiation-induced DNA damage without affecting DNA repair. This model has revealed that apoptosis and not arrest is likely to be responsible for growth inhibition. It also implicated new molecular targets and activities of the agents under conditions relevant to human exposure.
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PMID:Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. 1802 90

Although anticancer chemotherapeutic drugs have been designed to inhibit the growth of tumor cells, chemotherapy frequently fails due to the development of multidrug resistance (MDR). In this paper, the effect of survivin on multidrug resistance mediated by P-glycoprotein (Pgp) was investigated in breast cancer cells. Overexpression of survivin in MCF-7 cells transfected with survivin expression vector pEGFP/survivin results in decreasing sensitivity to anticancer drugs and activation of Pgp to export drug out of cells. Down regulation of survivin in MCF-7/adriamycin (ADR) transfected with RNAi directed against survivin vector psh1/survivin could increase the drug accumulation in cells by inhibiting Pgp. Downregulation of the expression of the Pgp with the specific inhibitor verapamil could markedly suppress the survivin mRNA expression, whereas the reverse impact was not observed. Survivin might modulate the turnover of Pgp or transport by Pgp in cells, which result in anti-apoptosis and drug resistance. Our results suggest that survivin might play a key role in MDR in the presence of Pgp, and this might represent a novel strategy for modulating MDR in cancer cells.
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PMID:The effect of survivin on multidrug resistance mediated by P-glycoprotein in MCF-7 and its adriamycin resistant cells. 1805 12


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