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)

The expressions of three mRNA markers were correlated with the results of extensive histopathological examination of a total of 290 axillary lymph nodes from 29 breast carcinoma patients. Included were two established markers for breast cancer (cytokeratin-19 and mammaglobin) and the novel marker DNA methyltransferase 3b (DNMT3b). DNMT3b was significantly overexpressed in breast cancer compared to normal breast tissue. The expression of the three markers in axillary lymph nodes was determined using quantitative real-time RT-PCR. DNMT3b expression showed a specificity of more than 99%, which was comparable to that of cytokeratin-19 and better than that of mammaglobin. The sensitivity of RT-PCR relative to histopathology was highest for cytokeratin-19 (96%), followed by DNMT3b (88%) and mammaglobin (68%). The overall agreement of histological and RT-PCR results was 96-99%. The results indicate that expression analysis of marker genes by quantitative RT-PCR can be a useful tool for lymph node diagnosis in breast cancer.
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PMID:Evaluation of three mRNA markers for the detection of lymph node metastases. 1709 13

Retinoic acids and their derivatives potentiate anti-cancer effects in breast cancer cells. The aberrant expression of telomerase is critical to the continued proliferation of most cancer cells. Thus, telomerase is an attractive target for chemoprevention and treatment of breast cancer. 9cUAB30 is a novel synthetic retinoid X receptor-selective retinoic acid (RA) that effectively reduces the tumorigenic phenotype in mouse breast carcinoma with lower toxic effects than natural retinoid treatments. We have assessed 9cUAB30 retinoic acid treatment of human breast cancer cells to determine the potential of this drug as an effective telomerase inhibitor and its application to cancer therapy. 9cUAB30 was found to decrease DNA methyltransferase and telomerase expression in MDA-MB-361, T-47D, and MCF-7 human breast cancer cells and to inhibit the proliferation of these cells. This low-toxicity retinoid also reduced colony formation in soft agar assays in each of these cell types. Combination treatments of 9cUAB30 and all-trans RA proved to be synergistically more effective than either RA alone, further suggesting a possible general epigenetic mechanism that contributes to the anti-telomerase activity of the retinoids. Therefore, the novel retinoid, 9cUAB30, is effective in inhibiting the growth of human breast cancer cells, its anti-cancer effects appear to be related to telomerase inhibition and the mechanism for this process could be mediated through epigenetic modifications.
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PMID:The low-toxicity 9-cis UAB30 novel retinoid down-regulates the DNA methyltransferases and has anti-telomerase activity in human breast cancer cells. 1727 65

The DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) inhibits DNA methyltransferase activity and sensitizes cancer cells to chemotherapy, but the mechanisms of its sensitization are not fully understood. Here, we show that 5-aza-CdR induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the human breast cancer MDA-231 cells. Induction of TRAIL by 5-aza-CdR correlated with inactivation of Akt. Furthermore, we show that overexpression of the active form of Akt by adenovirus infection or inhibition of the Akt downstream target glycogen synthase kinase 3 by its pharmacologic inhibitors abolishes TRAIL induction by 5-aza-CdR. Importantly, we show that the combined treatment of breast cancer cells with 5-aza-CdR and Adriamycin significantly increases apoptotic cell death compared with the treatment with either agent alone. Moreover, the combined treatment activated both death receptor and mitochondrial apoptotic pathways, whereas Adriamycin alone activated only the mitochondrial pathway while 5-aza-CdR failed to activate either. More importantly, down-regulation of TRAIL by small interference RNA silencing decreased 5-aza-CdR-mediated Adriamycin-induced caspase activation and apoptosis, thus conferring Adriamycin resistance. Taken together, our results suggest that induction of TRAIL by 5-aza-CdR is critical for enhancing chemosensitivity of breast cancer cells to Adriamycin.
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PMID:Evidence that tumor necrosis factor-related apoptosis-inducing ligand induction by 5-Aza-2'-deoxycytidine sensitizes human breast cancer cells to adriamycin. 1728 56

Increased risk for the development of endometrial cancer has been associated with unopposed oestrogen exposure, hyperoestrogenic factors, and a history of breast cancer treated long-term with tamoxifen (Tam). Stromal cell-derived factor-1, currently named as CXCL12, is a chemokine that, via binding to CXCR4 receptor, activates several downstream effectors and signalling pathways responsible for proliferation, survival, and migration of cancer cells. We observed that 17beta-estradiol (E2) and tamoxifen (Tam) increase the expression of CXCR4 and CXCL12 transcripts and proteins in oestrogen receptor positive (ER(+)) but not in negative (ER(-)02) Ishikawa endometrial adenocarcinoma (ISH) cell lines. However, the demethylating agent 5-Aza-2'-deoxycytidine profoundly elevated CXCR4 and CXCL12 expression in both ER(+) and ER(-)02 ISH cells. Bisulfite sequencing revealed that E2 and Tam up-regulate expression via demethylation of cytosine in the cytosine-guanosine dinucleotide island of CXCR4 and CXCL12 promoters. We also found that E2 and Tam significantly increased, for several hours, the expression of DNA methyltransferase 3B4 enzymatically inactive splice variant in ER(+) but not in ER(-)02 ISH cells. Our results suggest that E2 and Tam, through their ability for gene-transcription regulation, change the cellular milieu that maintains the hypermethylated stage of CpG islands of CXCR4 and CXCL12 promoters.
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PMID:Epigenetic up-regulation of CXCR4 and CXCL12 expression by 17 beta-estradiol and tamoxifen is associated with formation of DNA methyltransferase 3B4 splice variant in Ishikawa endometrial adenocarcinoma cells. 1736 37

It has been recently demonstrated that in colonic carcinoma, CXCL12 expression undergoes epigenetic regulation by methylation of cytosine in cytosine-guanosine (CpG) dinucleotides of the promoter sequence. Using lentiviral vectors, we generated stable RNA interference-mediated knockdown of DNMT1 and DNMT3B in MCF-7 breast cancer and AsPC1 pancreatic carcinoma cell lines. Employing reverse transcription real-time quantitative PCR and immunofluorescence analysis, we determined re-expression levels of CXCL12 transcript and protein in these cells. Bisulfite sequencing revealed that the level of promoter demethylation appeared more effective in cells expressing DNMT1 siRNA than in those expressing DNMT3B siRNA, and this correlated with higher expression of CXCL12. Moreover, the combined expression of DNMT1 and DNMT3B siRNAs enhanced promoter demethylation that was associated only with a slight increase of CXCL12 expression. However, the demethylating agent 5-Aza-2'-deoxycytidine exhibited the strongest effect on promoter demethylation, which correlated with the highest expression level of CXCL12 transcript and protein in MCF-7 and AsPC1 cells. Our findings suggest that DNMT1 plays a key role in maintenance of methylation, and DNMT3B may act as an accessory DNA methyltransferase to epigenetically silence CXCL12 expression in MCF-7 and AsPC1 cells.
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PMID:RNA interference-mediated knockdown of DNMT1 and DNMT3B induces CXCL12 expression in MCF-7 breast cancer and AsPC1 pancreatic carcinoma cell lines. 1753 57

Malignant breast cancer cells often exhibit lower expression and activity of manganese superoxide dismutase (MnSOD) than their normal cell counterparts; however, the mechanism(s) responsible for this change remains unclear. We examined whether SOD2, the gene encoding MnSOD, was epigenetically repressed in breast cancer cell lines by DNA methylation and histone acetylation. RT-PCR analysis of SOD2 mRNA showed the nontumorigenic breast epithelial cell line MCF-10A to have two to three fold higher expression levels than either UACC-893 or MDA-MB-435 breast carcinoma cells. Analysis of a region in the SOD2 promoter by sodium bisulfite genomic sequencing demonstrated significantly higher levels of CpG methylation in both human breast carcinoma cell lines assessed than in MCF-10A cells. CREB binding in vitro to a cognate site derived from this region was repressed by DNA methylation, and CREB binding to the 5' regulatory region of the SOD2 gene in vivo as determined by ChIP was significantly lower in breast carcinoma cells than in MCF-10A. Increased cytosine methylation was also accompanied by a significant decrease in the level of acetylated histones in the same region of the SOD2 promoter. Finally, a causal link between cytosine methylation and transcriptional repression was established by increasing MnSOD mRNA, protein and activity in breast carcinoma cells using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine. These findings indicate that epigenetic silencing of SOD2 constitutes one mechanism leading to the decreased expression of MnSOD observed in many breast cancers.
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PMID:Epigenetic regulation of manganese superoxide dismutase expression in human breast cancer cells. 1796 3

5-methylcytosine (m(5)C) can be used as a sensitive marker of progress of the tumor formation induced by the oxidative damage reactions. We have analyzed the amount of m(5)C in DNA of patients with breast and colon cancers. Two dimensional thin layer chromatography (TLC) has been used to monitor 5-methylcytosine level in DNA extracted from cancer tissues. The level of methylation of cytosine at C-5 position in DNA from breast cancer patients correlates well with the malignancy of tumors. Interestingly higher amount of m(5)C in DNA for the breast cancer patients treated with different chemotherapeutics was observed. It suggests an activation of DNA methyltransferase as well as a genomic suppression of the DNA repair genes expression. These differences clearly reflect the health condition of patients and support the global analysis of m(5)C in DNA as a good marker for diagnosis of neoplasia in clinical practice.
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PMID:Analysis of 5-methylcytosine in DNA of breast and colon cancer tissues. 1808 76

IFIXalpha, a member of the interferon-inducible HIN-200 family, has been identified as a putative tumor suppressor. However, the molecular mechanisms underlying IFIXalpha-mediated tumor suppression are poorly understood. In the present study, we demonstrated that the metastasis suppressor maspin acts as the downstream target of IFIXalpha. IFIXalpha suppressed the invasion activity of MDA-MB-468 breast cancer cells, and its inhibitory effect was reversed by the knockdown of maspin. Both Maspin mRNA and protein were upregulated by IFIXalpha. Histone deacetylase (HDAC) inhibitors, but not DNA methyltransferase inhibitor upregulated maspin, and HDAC1 inhibited the transactivation of maspin promoter. Although the HDAC1 protein was downregulated in IFIXalpha-expressing cells, IFIXalpha did not affect HDAC1 mRNA levels. Conversely, a proteasome inhibitor restored the level of HDAC1 protein in IFIXalpha-expressing cells, and the polyubiqutination of HDAC1 was promoted by IFIXalpha, suggesting that HDAC1 is regulated by IFIXalpha through a ubiquitin-proteasome pathway. Together, these data provide novel insights into the tumor-suppressive function of IFIXalpha.
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PMID:Interferon-inducible protein IFIXalpha inhibits cell invasion by upregulating the metastasis suppressor maspin. 1824 78

In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERalpha) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERalpha target genes silenced in ERalpha-negative mammary tumor cells. In cell lines derived from ERalpha-negative MDA-MB231 cells, stable expression of different levels of ERalpha from a transgene did not result in transcription of PR. A quantitative comparative analysis demonstrates that inhibiting DNA methyltransferases using 5-aza-2'-deoxycytidine or specific disruption of DNMT1 by small interfering RNAs and treatment with the histone-deacetylase inhibitor trichostatin A enabled ERalpha-mediated hormone-dependent expression of endogenous PR. We show that demethylation of a CpG island located in the first exon of PR was a prerequisite for ERalpha binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERalpha target genes involved in tumorigenesis. PR transcription did not subsist 4 days after removal of the DNA methyltransferase blocking agents, suggesting that hormone-induced expression of ERalpha target genes in ERalpha-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERalpha access to promoters.
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PMID:Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells. 1831 49

Because DNA methyltransferase (DNMT) inhibitors like azacytidine and decitabine are known to be effective in the clinic for diseases like myelodysplastic syndromes that may result in part from transcriptional dysregulation due to epigenetic changes, there is interest in developing novel DNMT inhibitors that would be more effective and less toxic. The effects of one such agent, zebularine, which inhibits DNMT and cytidine deaminase, were assessed in two human breast cancer cell lines, MDA-MB-231 and MCF-7. Zebularine treatment inhibited cell growth in a dose and time dependent manner with an IC-50 of approximately 100 microM and 150 microM in MDA-MB-231 and MCF-7 cells, respectively, on 96 h exposure. This was associated with increased expression of p21, decreased expression of cyclin-D, and induction of S-phase arrest. At high doses zebularine induced changes in apoptotic proteins in a cell line specific manner manifested by alteration in caspase-3, Bax, Bcl2 and PARP cleavage. Like other DNMT inhibitors, zebularine decreased expression of DNMTs post-transcriptionally as well as expression of other epigenetic regulators like methyl CpG binding proteins and global acetyl H3 and H4 protein levels. Its capacity to reexpress epigenetically silenced genes in human breast cancer cells at low doses was confirmed by its ability to induce expression of estrogen and progesterone receptor mRNA in association with changes suggestive of active chromatin at the ER promoter as evidenced by ChIP. Finally, its effect in combination with other DNMT or HDAC inhibitors like decitabine or vorinostat was explored. The combination of 50 muM zebularine with decitabine or vorinostat significantly inhibited cell proliferation and colony formation in MDA-MB-231 cells compared with either drug alone. These findings suggest that zebularine is an effective DNMT inhibitor and demethylating agent in human breast cancer cell lines and potentiates the effects of other epigenetic therapeutics like decitabine and vorinostat.
Breast Cancer Res Treat 2010 Apr
PMID:Effects of a novel DNA methyltransferase inhibitor zebularine on human breast cancer cells. 1945 41


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