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:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raloxifene, selective estrogen receptor (ER) modulator, is not fully explored in colorectal cancer. In the present study we, (a) investigated the effect of raloxifene on ER-positive colon cancer HCT-116 cell growth, (b) assessed the relevance of ER-beta in colon tumorigenesis, and (c) assessed the chemopreventive efficacy of raloxifene against azoxymethane (AOM)-induced colon carcinogenesis using aberrant crypt foci (ACF) as surrogate end point marker. HCT-116 cells treated with raloxifene showed a significant decrease in cell growth associated with a decrease in ER-beta expression levels. AOM-induced colon adenocarcinoma showed significant up-regulation of ER-beta expression at both the protein and mRNA levels compared with normal mucosa, suggesting that ER-beta is positively associated with colon cancer. An assay using five different dietary dose levels (0.31, 0.62, 1.25, 2.5, or 5 ppm) of raloxifene for 6 weeks in male F344 rats found the maximum tolerated dose to be 5 ppm. To evaluate inhibitory properties of raloxifene on colonic ACF, 7-week-old rats were fed experimental diets containing 0, 0.625, 1.25, and 2.5 ppm of raloxifene. After 1 week, rats received s.c. injections of AOM, 15 mg/kg body weight, once weekly for 2 weeks. Rats continued to receive respective experimental diets and sacrificed 8 weeks after the last AOM treatment. Raloxifene given in the diet significantly inhibited AOM-induced total colonic ACF (31-40%; P < 0.001-0.0005) and multicrypt (four or more) aberrant foci (23-50%; P < 0.05-0.005) in F344 rats. Our findings suggest that ER-beta acts as a colon tumor promoter and raloxifene as an antagonist to ER-beta, providing protection against colon carcinogenesis.
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PMID:Estrogen receptor-beta as a potential target for colon cancer prevention: chemoprevention of azoxymethane-induced colon carcinogenesis by raloxifene in F344 rats. 1913 18

The expression of the estrogen receptor beta (ERbeta) has been shown to play an important role in breast cancer. There is emerging hope that ERbeta and its isoforms will be used as prognostic markers or as therapeutic targets in the clinical management of breast cancer. Many studies indicate that ERbeta is down regulated during carcinogenesis. However, it is still unknown which signals can regulate ERbeta expression. Basement membrane (BM) components have been shown to influence the expression levels of ERalpha and progesterone receptor. Therefore, we hypothesized that cell-matrix interactions can also affect the expression of ERbeta and its isoforms. To test this we performed Matrigel assays using an ERalpha negative breast cancer cell line. MDA-MB-231 cells were plated on Matrigel, a reconstituted laminin-rich BM matrix, or on uncoated plastic culture plates. To investigate the effects of specific BM components we also cultured the cells on gels of purified collagen type IV and laminin-111. ERbeta expression levels were investigated after 24, 48 and 72 h by RT-PCRs which allow to distinguish between different ERbeta isoforms. MDA-MB-231 cells cultured on tissue culture plastic showed increased levels of ERbeta1 mRNA after 48 h. However, in cells cultured on Matrigel signals for ERbeta1 expression stayed at very low, nearly undetectable levels. Laminin-111 was identified to be the protein that represses ERbeta1 expression at the mRNA stage. Collagen type IV showed no effect on ERbeta expression. We further observed that MDA-MB-231 cells on Matrigel organize into cell aggregates which are connected in web-like structures that appear similar to lactiferous ducts. These data suggest that interactions of breast cancer cells with the BM protein laminin-111 suppress the expression of ERbeta1 at the mRNA level. A laminin-111-rich microenvironment seems to keep ERbeta1 at very low levels in breast cancer cells.
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PMID:A laminin-rich basement membrane matrix influences estrogen receptor beta expression and morphology of MDA-MB-231 breast cancer cells. 1914 25

Estrogen receptor beta (ERbeta) is widely expressed in mammary epithelium. ERbeta expression is reported to decline during carcinogenesis of the breast and other tissues. In this study, we examined the consequences of a loss of ERbeta expression in mammary epithelial cells. We knocked down ERbeta transcript levels in human mammary epithelial MCF-10A cells and in MCF-7 breast cancer cells by means of stable transfection with a specific shRNA plasmid. ERbeta knockdown resulted in a significant growth increase of both cell types in a ligand-independent manner. This effect was accompanied by elevated cyclin A2 expression in MCF-10A cells and by decreased expression of growth-inhibitory p21/WAF and epithelial cell marker cytokeratine 8 in both cell lines. Transfection of ERbeta shRNA did not alter the absent proliferative estrogen response of MCF-10A cells, but conferred sensitivity to selective estrogen receptor modulator tamoxifen to this cell line. In contrast, ERbeta knockdown diminished estrogen responsiveness of MCF-7 breast cancer cells and also weakened the effect of tamoxifen on this cell line. These ligand-dependent effects only observed in MCF-7 cells exhibiting a high ERalpha/beta ratio were accompanied by smaller estrogenic repression of p21/WAF expression, an impaired tamoxifen-triggered induction of this gene and by relative downregulation of ERalpha and cyclin A2 transcript levels. Our data suggest that ERbeta exerts antiproliferative effects both on MCF-10A and MCF-7 cells in a ligand- and ERalpha-independent manner by regulation of p21/WAF or cyclin A2 gene expression. Knockdown of ERbeta in both cell types was sufficient to significantly decrease transcript levels of epithelial cell marker cytokeratin 8. The results of this study support the hypothesis that ERbeta acts as a tumor suppressor in mammary epithelium.
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PMID:Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. 1943 90

The initial purpose of this study was to assess the role of estrogen receptor beta (ERbeta) in intestinal tumorigenesis by examining the effects of an ERbeta knockout (ERbeta(-/-)) on Apc(Min) mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERbeta knockout from the 129P2 genetic background to the B6 genetic background for 10 generations. Midway through this process, we performed a test cross in which mice from the N(5) backcross generation of the ERbeta knockout strain were intercrossed with Apc(Min/+) mice to obtain Apc(Min/+) ERbeta(+/+), Apc(Min/+) ERbeta(+/-) and Apc(Min/+) ERbeta(-/-) mice. Intestinal tumorigenesis in the N(5)F(2) mice was evaluated at 14 weeks of age. The analysis of the impact of ERbeta in the N(5) cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ERbeta. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in Apc(Min/+) mice. This locus, Modifier of Min 5 (Mom5), maps to proximal mouse chromosome 5; the 129P2 allele of this locus is associated with a 50% reduction in mean intestinal tumor number. Through in silico analysis and confirmatory sequencing, we have identified the Rad50-interacting protein-1 gene as a strong candidate for Mom5.
Carcinogenesis 2009 Sep
PMID:Genetic mapping of Mom5, a novel modifier of Apc(Min)-induced intestinal tumorigenesis. 1957 46

Sex significantly influences the clinical and pathological characteristics of colorectal cancer (CRC). These include differences in incidence and mortality rates, clinical presentations including age, emergency surgery for complications from CRC, screening participation rates, site, stage and treatment utilization, histopathology and survival. Environmental, behavioral and biological factors contribute to the differential risk. Recent advances in the molecular biology of CRC, specifically in microsatellite status, estrogen hormone and estrogen receptor beta, have led to greater understanding of the effect of estrogen in colorectal carcinogenesis. Estrogen may preferentially protect against microsatellite unstable cancers through its effect on selected molecular targets; however, the exact pathways have not been elucidated. Recognition of important sex disparities in these areas may lead to the implementation of specific measures to diminish these differences and facilitate equitable distribution of health resources. Identifying specific molecular targets on CRC that interact with estrogen may stimulate research to improve the overall outcomes of all patients with CRC.
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PMID:Sex differences in epidemiological, clinical and pathological characteristics of colorectal cancer. 1987 46

Most sporadic colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence pathway and are initiated by adenomatous polyposis coli (APC) gene mutations. Estrogen receptor beta (ERbeta) is recognized to progressively reduce its expression in adenomatous and carcinomatous tissues in humans. Moreover, ERbeta deficiency enhances small intestinal tumorigenesis in rodents. In the Apc(Min/+) mouse model, we evaluated intestinal polyp development and ERbeta expression plus other biological parameters influencing tumor growth (epithelial cell proliferation, apoptosis and migration) following the addition of a combination of the ERbeta-selective agonist silymarin (SIL) and/or lignin (LIG) to a high-fat/low-fiber diet. Forty-five Apc(Min/+) mice were divided in four groups: animals fed on the tumorigenic high-fat/low-fiber diet, the tumorigenic diet supplemented with SIL (0.02%) or purified LIG (6.24%) or SIL (0.005%) + LIG (6.24%). In these animals, we assessed polyp number and volume and their degree of dysplasia together with ERbeta messenger RNA (mRNA) and protein levels and epithelial cell proliferation, migration and apoptosis. The latter group of parameters was evaluated in normal and adenomatous mucosa and the results compared with those found in wild-type (WT) mice fed on the control diet. The addition of SIL or LIG to the diet and even more the specific combination of the two significantly counteracted intestinal tumorigenesis and increased ERbeta mRNA and protein levels. Cell proliferation and apoptosis were rebalanced and cell migration accelerated, restoring values similar to those observed in WT animals. Our results further support a protective effect of ERbeta in CRC suggesting the use of the combination of SIL-LIG as a potential approach against CRC development.
Carcinogenesis 2010 Feb
PMID:Dietary-induced ERbeta upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice. 1994 67

The estrogen signal is mediated by the estrogen receptor (ER). The specific role of ER-beta, a second ER, in breast carcinogenesis is not known. A number of association studies have been carried out to investigate the relationship between polymorphic sites in the ESR2 gene and breast cancer risk, however, the results are inconsistent. We searched PubMed, Medline, and Web of Science database (updated to 10 January 2010) and identified 13 relevant case-control studies, and approximately 28 single-nucleotide polymorphisms (SNPs) and one micro-satellite marker were reported in the literature. The median number of study subjects was 776 (range 158-13,550). Three genetic variants [(CA)n, rs2987983, and rs4986938] showed significant overall associations with breast cancer, and rs4986938 was reported twice. Because rs4986938 and rs1256049 were the most extensively studied polymorphisms, we subsequently conducted a meta-analysis to evaluate their relationship with breast cancer risk (9 studies of 10,837 cases and 16,021 controls for rs4986938; 8 studies of 11,652 cases and 15,726 controls for rs1256049). For rs4986938, the women harboring variant allele seemed to be associated with a decreased risk either in the dominant model [pooled OR = 0.944, 95% confidence interval (95% CI) 0.897-0.993, fixed-effects] or in the co-dominant model (AG vs. GG) (OR = 0.944, 95% CI 0.895-0.997, fixed-effects). rs1256049 was not associated with breast cancer risk in any model. Five studies had investigated the effect of haplotypes in the ESR2 gene on breast cancer risk, and four of them had positive outcomes. In summary, the present systematic review suggests that SNP rs4986938 as well as haplotypes in the ESR2 gene might be associated with breast cancer. The need for additional studies examining these issues seems of vital importance.
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PMID:A systematic review of the relationship between polymorphic sites in the estrogen receptor-beta (ESR2) gene and breast cancer risk. 2039 Mar 41

This perspective on Jin et al. (beginning on page 910 in this issue of the journal) discusses the importance of estrogen signaling in colorectal carcinogenesis, with a focus on estrogen receptor beta (ERbeta), which is the predominant ER in the colorectal epithelium. The importance of ERbeta in breast cancer is well described in the literature, and recent studies reveal that ERbeta functions similarly in colorectal cancer. The implications of this pathway include new possibilities to treat or prevent colorectal cancer with targeted endocrine drugs and the potential of ERbeta as a novel diagnostic tool.
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PMID:Estrogen receptors in colorectal cancer: goalkeepers, strikers, or bystanders? 2066 78

The role of the estrogen receptor beta (ERbeta) in the colon has received considerable interest, yet in vivo models are needed to better define its protective actions. In the present study, wild-type (WT), ERalpha, and ERbeta knockout (alphaERKO and betaERKO) mice were injected with azoxymethane, a colon chemical carcinogen. Fourteen weeks after azoxymethane exposure, the incidence of aberrant crypt foci (ACF) was assessed by methylene blue staining. betaERKO mice showed significantly higher incidence (P < 0.001) of ACF (15.0 +/- 2.5) compared with alphaERKO (3.4 +/- 1.0) and WT (4.6 +/- 1.0) mice. The colons in several betaERKO mice had increased thickness and loss of normal morphology. It has been reported that ERbeta plays a role in the maintenance of the colonic crypt architecture; this may explain the loss of crypt organization in the colonic epithelium of betaERKO mice. The presence of mucin-depleted foci (MDF) has been shown, both in humans and in rodents, as an early event in colon cancer. Therefore, to surpass the limitations with ACF scoring, we performed Alcian blue-neutral red staining to assess the presence of MDF. This assay allowed the assessment of precancerous lesions on all the betaERKO mice colons (38.3 +/- 4.0; P < 0.001), comparing to WT and alphaERKO mice (6.6 +/- 1.5 and 10.0 +/- 1.9, respectively), and served to confirm the ACF results. Together, these data support the use of MDF staining as a biomarker for precancerous lesions and the protective role of ERbeta in colon carcinogenesis.
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PMID:Enhanced induction of mucin-depleted foci in estrogen receptor {beta} knockout mice. 2071 34

The metastasis-associated gene MTA3 has an important function in invasion and metastasis of human cancer cells. Therefore, the aim of this study was to investigate the expression of this protein in endometrial adenocarcinomas and to analyse potential correlations between this nuclear transcription factor and estrogen receptors in endometrial adenocarcinomas. Additionally, we evaluated whether MTA3 might be a prognostic parameter in endometrioid adenocarcinomas. Endometrioid adenocarcinomas were obtained from 200 patients and immunohistochemically analysed for MTA3 and estrogen receptor alpha and beta (ER-alpha and ER-beta) expression. Overall, endometrioid adeno-carcinomas of histological differentiation grade 3 demonstrated a significantly lower expression of MTA3 compared to carcinomas of histological grade 1 and 2 (p<0.05). MTA3 expression is reduced in endometrioid adenocarcinomas of poor differentiation, though without any correlation to ER-alpha and ER-beta expression. Furthermore, the expression of MTA3 did not affect progression-free, cause-specific and overall survival. Overall, MTA3 did not constitute an independent prognostic factor in this study, suggesting that MTA3 is not a useful marker to assess and identify high-risk patients with endometrial adenocarcinomas. Still, the downregulation of MTA3 predispose this cell type to be of high metastatic potential after malignant transformation, playing an essential, but as yet unknown role in human endometrial carcinogenesis.
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PMID:The metastasis-associated gene MTA3 is downregulated in advanced endometrioid adenocarcinomas. 2086 67


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