Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The candidate human tumor suppressor gene cyclin C is a primary target of the anti-proliferative hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], but binding sites for the 1alpha,25(OH)2D3 receptor (VDR), so-called 1alpha,25(OH)2D3 response elements (VDREs), have not yet been identified in the promoter of this gene. We screened various cancer cell lines by quantitative PCR and found that the 1alpha,25(OH)2D3 inducibility of cyclin C mRNA expression, in relationship with the 24-hydroxylase (CYP24) gene, was best in MCF-7 human breast cancer cells. To characterize the molecular mechanisms, we analyzed 8.4 kb of the cyclin C promoter by using chromatin immunoprecipitation assays (ChIP) with antibodies against acetylated histone 4, VDR and its partner receptor, retinoid X receptor (RXR). The histone 4 acetylation status of all 23 investigated regions of the cyclin C promoter did not change significantly in response to 1alpha,25(OH)2D3, but four independent promoter regions showed a consistent, 1alpha,25(OH)2D3-dependent association with VDR and RXR over a time period of 240 min. Combined in silico/in vitro screening identified in each of these promoter regions a VDRE and reporter gene assays confirmed their functionality. Moreover, re-ChIP assays monitored simultaneous association of VDR with RXR, coactivator, mediator and RNA polymerase II proteins on these regions. Since cyclin C protein is associated with those mediator complexes that display transcriptional repressive properties, this study contributes to the understanding of the downregulation of a number of secondary 1alpha,25(OH)2D3-responding genes.
 ...
PMID:Regulation of the human cyclin C gene via multiple vitamin D3-responsive regions in its promoter. 1586 22

The main regulator of the human tumor suppresser gene p21(waf1/cip1) is the transcription factor p53, but more recently it has been suggested to be a primary anti-proliferative target for the nuclear receptor VDR in the presence of its ligand 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3). To identify VDR responding regions, we analyzed 20 overlapping regions covering the first 7.1 kb of the p21(waf1/cip1) promoter in MCF-7 human breast cancer cells using chromatin immuno-precipitation assays (ChIP) with antibodies against p53 and VDR. We confirmed two known p53 binding regions at approximate positions -1400 and -2300 and identified a novel site at position -4500. In addition, we found three VDR-associated promoter regions at positions -2300, -4500 and -6900, i.e. two regions showed binding for both p53 and VDR. In silico screening and in vitro binding assays using recombinant and in vitro translated proteins identified five p53 binding sites within the three p53-positive promoter regions and also five 1alpha,25(OH)2D3 response elements within the three VDR-positive regions. Reporter gene assays confirmed the expected responsiveness of the respective promoter regions to the p53 inducer 5-fluorouracil and 1alpha,25(OH)2D3. Moreover, re-ChIP assays confirmed the functionality of the three 1alpha,25(OH)2D3-reponsive promoter regions by monitoring simultaneous occupancy of VDR with the co-activator proteins CBP, SRC-1 and TRAP220. Taken together, we demonstrated that the human p21((waf1/cip1)) gene is a primary 1alpha,25(OH)2D3-responding gene with at least three VDR binding promoter regions, in two of which also p53 co-localizes.
 ...
PMID:Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. 1643 1

We investigated inherited polymorphic variation in genes spanning estrogen metabolism (10 SNPs [single nucleotide polymorphism]) to distinguish multilocus genotypes associated with breast cancer (n = 393), benign breast lesions (n = 154), and low risk (n = 1936). Three latent classification GoM extreme type groups represented the data: (a) fibroadenoma, and infrequent SRD5A2 and VDR alleles; (b) postmenopausal breast cancer, and infrequent CYP1A1-1 and CYP1A1-2 alleles (both over-represented infrequent alleles for CYP17, CYP19-3, and COMT); and (c) women at intrinsically low risk. Carriage of the respective multilocus genotypes increased risk 25-fold. We conclude that GoM latent classification may be useful to identify genetic risk sets and estimate risk for individuals.
 ...
PMID:Multilocus genotypes spanning estrogen metabolism associated with breast cancer and fibroadenoma. 1660 96

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency single nucleotide polymorphisms (SNPs) has increased in recent years. Evidence is accumulating defining specific individual variations in breast cancer susceptibility. Genetic variations of estradiol and xenobiotics metabolisms as well as genes involved in cell-cycle control have been described as significant contributors to breast cancer susceptibility, with variations depending on ethnic background and co-factors such as smoking and family history of breast cancer. In sum, the highest level of evidence to date linking SNPs and breast cancer comes from nested case-control studies within the prospective Nurses' Health Study. These data establish seven SNPs - hPRB +331G/A, AR CAG repeat, CYP19 (TTTA)10, CYP1A1 MspI, VDR FOK1, XRCC1 Arg194Trp and XRCC2 Arg188His - as small but significant risk factors for spontaneous, non-hereditary breast cancer. In addition, meta-analysis of data in the literature establishes the TGFBR1*6A, HRAS1, GSTP Ile105Val and GSTM1 SNPs as low-penetrance genetic risk factors of sporadic breast cancer. The clinical consequences of such a risk elevation may be detailed instruction of the patient as to general measures of breast cancer prevention such as a low-fat diet, optimization of body mass index, physical exercise, avoidance of alcohol and long-term hormone replacement therapy, and participation in a breast cancer screening program between the ages of 50 and 70 years. Specific surgical or drug interventions such as prophylactic mastectomy and oophorectomy or prophylactic intake of tamoxifen are not indicated based on SNP analysis at this time.
 ...
PMID:How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer? 1683 78

Our previous microarray analysis showed that N-methyl-N-nitrosourea (MNU) transformed MCF12F breast epithelial cells exhibited upregulation of several genes, including prohibitin, which was reversed by 1alpha-hydroxyvitamin D(5) (1alpha(OH)D(5)) treatment. The in silico screening for putative transcription factor binding sites identified two VDR/RXR binding sites in the 1kb promoter region of prohibitin. Other binding sites for EGR and GR which are also Vitamin D target genes were identified in this region, indicating that prohibitin is a potential target gene for Vitamin D. The combination of multiple binding sites also provides a basis for a possible dual regulation of prohibitin by Vitamin D. Prohibitin upregulation by 1alpha(OH)D(5) treatment at both transcription and translation level was observed in Vitamin D sensitive BT474 breast cancer cells, in which 1alpha(OH)D(5) significantly inhibited cell proliferation in normal culture condition. On the other hand, prohibitin down-regulation accompanied with Vitamin D mediated maintenance of proliferation of breast epithelial cells was observed under stressed condition. These results demonstrated that Vitamin D mediated antiproliferative activity in unstressed condition and growth maintaining activity under stressed condition involve differential expression of prohibitin.
 ...
PMID:Differential expression of prohibitin is correlated with dual action of Vitamin D as a proliferative and antiproliferative hormone in breast epithelial cells. 1720 17

The human 25-hydroxyvitamin D3 (25(OH)D3) 1alpha-hydroxylase, which is encoded by the CYP27B1 gene, catalyzes the metabolic activation of the 25(OH)D3 into 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), the most biologically potent vitamin D3 metabolite. The most important regulator of CYP27B1 gene activity is 1alpha,25(OH)2D3 itself, which down-regulates the gene. The down-regulation of the CYP27B1 gene has been proposed to involve a negative vitamin D response element (nVDRE) that is located approximately 500 bp upstream from transcription start site (TSS). In this study, we reveal the existence of two new VDR-binding regions in the distal promoter, 2.6 and 3.2 kb upstream from the TSS, that bind vitamin D receptor-retinoid X receptor complexes. Since the down regulation of the CYP27B1 gene is tissue- and cell-type selective, a comparative study was done for the new 1alpha,25(OH)2D3-responsive regions in HEK-293 human embryonic kidney and MCF-7 human breast cancer cells that reflect tissues that, respectively, are permissive and non-permissive to the phenomenon of 1alpha,25(OH)2D3-mediated down-regulation of this gene. We found significant differences in the composition of protein complexes associated with these CYP27B1 promoter regions in the different cell lines, some of which reflect the capability of transcriptional repression of the CYP27B1 gene in these different cells. In addition, chromatin architecture differed with respect to chromatin looping in the two cell lines, as the new distal regions were differentially connected with the proximal promoter. This data explains, in part, why the human CYP27B1 gene is repressed in HEK-293 but not in MCF-7 cells.
 ...
PMID:Selective use of multiple vitamin D response elements underlies the 1 alpha,25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene. 1742 22

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the most active metabolite of vitamin D, exerts its biological effects by binding to a specific intracellular receptor (the vitamin D receptor, VDR) present in target cells. 1,25-(OH)(2)D(3) is involved in a host of cell processes, including calcium homeostasis, cell growth and differentiation, and secretion of hormones. Several studies have explored the role of 1,25-(OH)(2)D(3) in cell growth and differentiation in normal and tumoral mammary gland, in which it shows antiproliferative effects. These effects have been attributed to suppression of growth-stimulatory signals and potentiation of growth-inhibitory signals, leading to changes in cell-cycle regulators as well as to induction of apoptosis. In apparent contrast to these antiproliferative effects, however, several studies have suggested that breast tumor formation may be related to the autocrine/paracrine effects of growth hormone (GH) and prolactin (PRL). The pituitary transcription factor-1 (Pit-1), which in the pituitary is critical to both cell differentiation and PRL and GH transcription, has been recently found in normal and tumoral human breast tissue, with mRNA expression levels significantly higher in tumors than in normal breast. As in the pituitary, Pit-1 regulates mammary GH and PRL secretion, increases cell proliferation and decreases apoptosis. 1,25-(OH)(2)D(3) administration to the MCF-7 human breast adenocarcinoma cell line significantly reduces Pit-1 expression, suggesting that inhibition of Pit-1 expression by 1,25-(OH)(2)D(3) may reduce the increase in proliferation induced by this transcription factor directly or indirectly through increased GH and/or PRL expression. In this review, we evaluate the role of 1,25-(OH)(2)D(3) and Pit-1/PRL/GH in human breast, and consider the relationships between these factors in normal mammary development and in breast cancer.
 ...
PMID:Vitamin D, Pit-1, GH, and PRL: possible roles in breast cancer development. 1822 Jul 41

The aim of the study was to determine whether four VDR gene single nucleotide polymorphisms (SNPs: rs1544410, rs731236, rs10735810 and rs4516035) are associated with breast cancer risk in Polish population. Two independent series of female patients were employed: 960 consecutive breast cancer cases, and 800 unselected early onset cases diagnosed under the age of 51. The control group for the consecutive breast cancer cases consisted of 960 healthy, age-matched women with a negative cancer family history. 550 healthy women, aged 51 or less, with negative cancer family history were selected as the independent controls for the early onset breast cancer cases. The frequencies of the VDR polymorphisms in the unselected cases when compared to the respective control population failed to reveal any association between the individual SNPs and disease. Examination of the group of early-onset patients, revealed an association between rs10735810 and increased breast cancer risk. Heterozygous carriers for the change had an OR = 1.73 (95% CI 1.33-2.26, P < 0.0001) and homozygous carriers OR = 2.34 (95% CI 1.71-3.21, P < 0.0001). The remaining three examined SNPs failed to show any association with disease risk. In summary, this study has identified an association between the VDR gene and early onset breast cancer risk in the Polish population.
Breast Cancer Res Treat 2009 Jun
PMID:Vitamin D receptor variants and breast cancer risk in the Polish population. 1858 72

Numerous studies have shown that the active form of vitamin D, 1,25(OH)(2)D(3), can exert growth inhibitory effects on human breast cancer cells and mammary tumor growth. However, the molecular mechanisms remain to be fully delineated. This study demonstrates for the first time that CCAAT enhancer-binding protein alpha (C/EBPalpha), a member of the C/EBP family of transcription factors, is induced by 1,25(OH)(2)D(3) and is a potent enhancer of VDR transcription in MCF-7 breast cancer cells. 1,25(OH)(2)D(3) was found to induce C/EBPalpha as well as VDR expression in MCF-7 cells. C/EBPalpha was not detected in MDA-MB-231 cells that are poorly responsive to 1,25(OH)(2)D(3). Antiproliferative effects of 1,25(OH)(2)D(3) and induction of VDR were observed in MDA-MB-231 cells transfected with C/EBPalpha, and knockdown of C/EBPalpha suppressed VDR and antiproliferative effects of 1,25(OH)(2)D(3) in MCF-7 cells. Transfection of C/EBPalpha in MCF-7 cells resulted in a dose-dependent enhancement of hVDR transcription. Our studies show that C/EBPalpha can bind to Brahma (Brm), an ATPase that is a component of the SWI/SNF complex, and cooperate with Brm in the regulation of hVDR transcription in MCF-7 cells. Because the levels of VDR in MCF-7 breast cancer cells correlate with the antiproliferative effects of 1,25(OH)(2)D(3) and because C/EBPalpha has been suggested as a potential tumor suppressor in breast cancer, these findings provide important mechanisms whereby 1,25(OH)(2)D(3) may act to inhibit growth of breast cancer cells. These findings also identify C/EBPalpha as a 1,25(OH)(2)D(3) target in breast cancer cells and provide evidence for C/EBPalpha as a candidate for breast cancer treatment.
 ...
PMID:CCAAT enhancer-binding protein alpha is a molecular target of 1,25-dihydroxyvitamin D3 in MCF-7 breast cancer cells. 1905 66

Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software.
 ...
PMID:Sibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic density. 1991 59


<< Previous 1 2 3 4 5 6 7 8 Next >>