UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physical activity reduces breast cancer risk. Promoter hypermethylation of the tumor suppressor genes APC and RASSF1A, which is potentially reversible, is associated with breast cancer risk. We conducted a cross-sectional study in 45 women without breast cancer to determine the association of physical activity with promoter hypermethylation of APC and RASSF1A in breast tissue. We used quantitative methylation-specific PCR to test the methylation status of APC and RASSF1A, and questionnaires to assess study covariates and physical activity (measured in metabolic equivalent hours per week). In univariate analyses, the study covariate, benign breast biopsy number, was positively associated with promoter hypermethylation of APC (P = 0.01) but not RASSF1A. Mulitvariate logistic regression indicated that, although not significant, physical activities for a lifetime [odds ratio (OR), 0.57; 95% confidence interval (95% CI), 0.22-1.45; P = 0.24], previous 5 years (OR, 0.62; 95% CI, 0.34-1.12; P = 0.11), and previous year (OR, 0.72; 95% CI, 0.43-1.22; P = 0.22) were inversely related to promoter hypermethylation of APC but not RASSF1A for all physical activity measures. Univariate logistic regression indicated that physical activities for a lifetime, previous 5 years, and previous year were inversely associated with benign breast biopsy number, and these results were approaching significance for lifetime physical activity (OR, 0.41; 95% CI, 0.16-1.01; P = 0.05) and significant for physical activity in the previous 5 years (OR, 0.57; 95% CI, 0.34-0.94; P = 0.03). The study provides indirect evidence supporting the hypothesis that physical activity is inversely associated with promoter hypermethylation of tumor suppressor genes, such as APC, in nonmalignant breast tissue.
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PMID:Role of physical activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in nonmalignant breast tissue. 1730 Dec 49

Protein C inhibitor (PCI) regulates the anticoagulant protein C pathway and also inhibits urinary plasminogen activator (uPA), a mediator of tumor cell invasion. In the present study, we evaluated the effect of human PCI and its inactive derivatives on tumor growth and metastasis of human breast cancer (MDA-231) cells, and on angiogenesis in vivo. The invasiveness of MDA-231 cells was inhibited by recombinant intact PCI, but not by reactive site-modified PCI (R354APCI) or by the N-terminal fragment of protease-cleaved PCI (NTPCI). The in vitro invasiveness of MDA-231 cells expressing intact PCI (MDA-PCI) was significantly decreased as compared to MDA-231 cells expressing R354APCI (MDA-R354APCI) or NTPCI (MDA-NTPCI). Further, in vivo growth and metastatic potential of MDA-PCI, MDA-R354APCI and MDA-NTPCI cells in severe combined immunodeficient (SCID) mice were significantly decreased as compared to MDA-Mock cells. Angiogenesis was also significantly decreased in Matrigel implant containing MDA-PCI, MDA-R354APCI or MDA-NTPCI cells as compared to that containing MDA-Mock cells. In vivo angiogenesis in rat cornea and in vitro tube formation were also inhibited by recombinant intact PCI, R354APCI and NTPCI. Furthermore, the anti-angiogenic activity of PCI was strong as cleaved antithrombin (AT), and slightly stronger than that of plasminogen activator inhibitor (PAI)-1 and pigment epithelium-derived factor (PEDF). Overall, this study showed that, in addition to a reactive site-dependent mechanism, PCI may also regulate tumor growth and metastasis independently of its protease inhibitory activity by inhibiting angiogenesis.
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PMID:Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity. 1745 May 26

Aberrant methylation of promoter CpG islands is causally linked with a number of inherited syndromes and most sporadic cancers, and may provide valuable diagnostic and prognostic biomarkers. In this report, we describe an approach to simultaneous analysis of multiple CpG islands, where methylation-specific oligonucleotide probes are joined by ligation and subsequently amplified by polymerase chain reaction (PCR) when hybridized in juxtaposition on bisulfite-treated DNA. Specificity of the ligation reaction is achieved by (i) using probes containing CpGpCpG (for methylated sequences) or CpApCpA (for unmethylated sequences) at the 3' ends, (ii) including three or more probes for each target, and (iii) using a thermostable DNA ligase. The external probes carry universal tails to allow amplification of multiple ligation products using a common primer pair. As proof-of-principle applications, we established duplex assays to examine the FMR1 promoter in individuals with fragile-X syndrome and the SNRPN promoter in individuals with Prader-Willi syndrome or Angelman syndrome, and a multiplex assay to simultaneously detect hypermethylation of seven genes (ID4, APC, RASSF1A, CDH1, ESR1, HIN1 and TWIST1) in breast cancer cell lines and tissues. These data show that ligation of oligonucleotide probes hybridized to bisulfite-treated DNA is a simple and cost-effective approach to analysis of CpG methylation.
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PMID:A ligation assay for multiplex analysis of CpG methylation using bisulfite-treated DNA. 1799 53

The average length of linkage disequilibrium (LD) blocks in European populations is about 22 kb. In this study, we have selected 20 genes with LD blocks larger than 60 kb (with a median length of 88 kb) from a total of 121 cancer-related genes. We observed limited haplotype diversity, with an average of three haplotypes per gene accounting for more than 90% of the diversity, two of these being a Yin-Yang pair in 95% of the LD blocks. The mean frequency of the most common haplotype in the Spanish population was just below 50%, similar to those for the HapMap CEU and African samples, but lower than the 60% observed in Asian samples. Genes involved in the regulation of nucleobases and nucleic acid metabolism were overrepresented among these 20 genes with long LD blocks (eight genes ATM, BRCA1, BRCA2, ERCC6, MLH1, MSH3, RAD54B and XRCC4) relative to the other 101 cancer-related genes studied (P=1.23 x 10(-6)). The ancestral haplotype was observed at a frequency greater than 3 in 67% of the genes either in the Spanish or one of the HapMap sampled populations. When observed, the ancestral haplotype had an average 15% frequency in the Spanish sample, less than half that observed in Asian and African samples. The Spanish Yin-Yang haplotype pair represented over 35% of haplotypes in African samples and over 65% in non-African samples. We detected differences in SNP frequencies between populations for five genes (ALDH2, APC, PIK3CB, RB1 and XRCC4, all with Fst>0.4); however, these genes did not show evidence of positive selection. Finally, we found no evidence that the haplotypes formed by SNPs in the 20 genes are associated with breast cancer.
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PMID:Haplotype patterns in cancer-related genes with long-range linkage disequilibrium: no evidence of association with breast cancer or positive selection. 1800 May 25

Activated protein C (APC) and protein C inhibitor (PCI) are the major components of the anticoagulant protein C pathway. Recently, APC and PCI have been demonstrated to play many roles not only in the regulation of hemostasis but also in cell inflammation, proliferation, apoptosis, tumor cell migration, invasion, and metastasis. Here we summarize the role of APC and PCI in malignancy. APC increases migration of ovarian cancer cells and choriocarcinoma cells in a Transwell invasion assay in the presence of plasminogen activator inhibitor (PAI)-1; this finding suggests that APC stimulates urokinase-type plasminogen activator (uPA) by forming a complex with PAI-1 leading to activation of extracellular matrix proteases and increased invasion. It was recently reported that APC, independent of PAI-1, may increase invasion and chemotaxis of breast cancer cells by activating specific signaling pathways through endothelial protein C receptor (EPCR) and protease-activated receptor (PAR)-1. APC also increased proliferation of vascular endothelial cells and angiogenesis by EPCR-mediated activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and endothelial nitric oxide synthase (eNOS) pathways. On the other hand, we have previously reported that both uPA and PCI are synthesized in renal proximal tubular epithelial cells (RPTECs) and that PCI expression in RPTEC-derived tumor cells is significantly decreased compared with normal RPTECs. The RPTEC-derived renal carcinoma cell line Caki-1 also showed decreased expression of PCI. PCI inhibited in vitro invasive activity of Caki-1 and breast cancer cells by its protease inhibitory activity. However, PCI was found to inhibit the growth and metastatic potential of breast cancer cells independent of its protease inhibitory activity in severe combined immunodeficient mice. PCI can also inhibit angiogenesis in vivo and in vitro assays independent of its protease inhibitory activity. Overall, these data show that APC promotes tumor cell invasion by EPCR-mediated and PAR-1-mediated protease activity and that PCI inhibits tumor cell invasion in vitro by its protease inhibitory activity and suppresses tumor cell growth, metastasis, and angiogenesis independent of its protease inhibitory activity.
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PMID:Protein C and its inhibitor in malignancy. 1800 Jul 93

The effects of 2-chloro-2'-deoxyadenosine, 9-beta-D-arabinofuranosyl-2-fluoroadenine, and 5-aza-2'-deoxycytidine on promoter methylation of the selected tumor suppressor genes (i.e., ERalpha, BRCA1, RARbeta2, E-cadherin, PTEN, and APC) were estimated using methylation-sensitive restriction analysis. The studies were carried out in hormone-responsive, low-invasive cell line MCF-7 and hormone-insensitive, highly invasive cell line MDA-MB-231. The results demonstrate an implication of the tested adenosine analogues and 5-aza-dCyd in regulation of DNA methylation process. Moreover, the effects of nucleoside analogues on PTEN promoter methylation suggest distinct mechanism of regulation of the epigenetic DNA modification in low-invasive compared to highly invasive breast cancer cells.
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PMID:The effects of nucleoside analogues on promoter methylation of selected tumor suppressor genes in MCF-7 and MDA-MB-231 breast cancer cell lines. 1805 33

Although mutation of APC or CTNNB1 (beta-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a beta-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis.
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PMID:Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. 1828 16

The aim of the present study was to investigate the association between gene hypermethylation and main clinicopathological features of breast cancer, including diagnosis and treatment response. A sensitive SYBR green methylation-specific PCR technique was used to analyze the utility of circulating DNA with CpG island hypermethylation of ESR1, APC, RARB, 14-3-3-sigma and E-cad gene promoter regions as breast cancer biomarkers. Analyses were conducted of preoperative sera from 106 women with breast cancer, 34 with benign breast disease and 74 with no evidence of breast disease and of post-treatment sera from 60 of the breast cancer patients. Mean serum values of methylated ESR1 and 14-3-3-sigma gene promoters significantly differed between breast cancer patients and healthy controls (p = 0.0112 for ESR1 and p = 0.0047 for 14-3-3-sigma). When their results were combined, it was found that hypermethylation of these two genes differentiated between breast cancer patients and healthy controls (p < 0.0001) with a sensitivity of 81% (95% confidence interval: 72-88%) and specificity of 88% (95% CI: 78-94%). Presence of methylated ESR1 in serum of breast cancer patients was associated with the ER negative phenotype (p = 0.0179). Serum hypermethylation at ESR1 and 14-3-3-sigma loci was observed in cancer patients, in situ carcinoma and benign breast disease. No significant differences in methylated ERS1 or 14-3-3-sigma values were observed between pre-surgery and post-treatment measurements. Preliminary clinical applications of this approach have revealed several shortcomings, including a frequent presence of methylated 14-3-3-sigma in sera from women with breast benign disease. These findings cast some doubts on the utility for early cancer diagnosis of highly sensitive techniques to identify hypermethylation of specific gene promoters in DNA extracted from serum. Although numerous issues remain to be resolved, the quantitative measurement of circulating methylated DNA remains a promising tool for cancer risk assessment.
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PMID:Quantitative detection of methylated ESR1 and 14-3-3-sigma gene promoters in serum as candidate biomarkers for diagnosis of breast cancer and evaluation of treatment efficacy. 1837 96

Breast cancer is one of the most common malignancies in women. Despite advances in treatment of endocrine-dependent tumors, the complete molecular basis of transformation is still unknown. What is clear is that a variety of genetic lesions and epigenetic modifications are present in the neoplasm. Disregulation of several signaling pathways is known to be associated with breast cancer development, among them is the wingless and integration site growth factor (Wnt) pathway. While genetic mutations of certain components of this pathway, such as APC, are significant contributing factors for colorectal cancers, they are typically not the predominate mechanism associated with breast cancer. Instead, it appears that DNA hypermethylation leads to aberrant regulation of the Wnt pathway in breast cancer, and as such, this review focuses on the epigenetic regulation of Wnt pathway components in breast cancer.
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PMID:Epigenetic gene silencing in the Wnt pathway in breast cancer. 1839 11

Aberrant Wnt/beta-catenin signaling leading to nuclear accumulation of the oncogene product beta-catenin is observed in a wide spectrum of human malignancies. The destruction complex in the Wnt/beta-catenin pathway is critical for regulating the level of beta-catenin in the cytoplasm and in the nucleus. Here, we report a comprehensive study of the contribution of genetic variation in six genes encoding the beta-catenin destruction complex (APC, AXIN1, AXIN2, CSNK1D, CSNK1E, and GSK3B) to breast cancer using a Mayo Clinic Breast Cancer Case-Control Study. A total of 79 candidate functional and tagging single nucleotide polymorphisms (SNP) were genotyped in 798 invasive cases and 843 unaffected controls. Of these, rs454886 in the APC tumor suppressor gene was associated with increased breast cancer risk (per allele odds ratio, 1.23; 95% confidence intervals, 1.05-1.43; P(trend) = 0.01). In addition, five SNPs in AXIN2 were associated with increased risk of breast cancer (P(trend) < 0.05). Haplotype-based tests identified significant associations between specific haplotypes in APC and AXIN2 (P < or = 0.03) and breast cancer risk. Further characterization of the APC and AXIN2 variants suggested that AXIN2 rs4791171 was significantly associated with risk in premenopausal (P(trend) = 0.0002) but not in postmenopausal women. The combination of our findings and numerous genetic and functional studies showing that APC and AXIN2 perform crucial tumor suppressor functions suggest that further investigation of the contribution of AXIN2 and APC SNPs to breast cancer risk are needed.
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PMID:Association of genetic variation in genes implicated in the beta-catenin destruction complex with risk of breast cancer. 1870 3

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