Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Consumption of soy foods has been weakly associated with reduced colon cancer risk. Colon cancer risk is influenced by estrogen exposure, although the mechanism through which this occurs is not defined. Conversion of estradiol (E2) to estrone (E1) may be protective in the colon. We hypothesized that dietary phytoestrogens, or E1, would reduce colon tumorigenesis via an estrogen receptor (ER)-dependent mechanism. Ovariectomized ERalphaKO or wild-type (WT) female mice were fed diets containing casein (Casein), soy protein without isoflavones (Soy-IF), soy protein + genistein (Soy+Gen), soy protein + NovaSoy (Soy+NSoy) or soy protein + estrone (Soy+E1) from weaning. Colon tumors were induced with azoxymethane. Tumor incidence was affected by diet but not genotype. Colon tumor incidence was lower in ERalphaKO and WT mice fed the Soy+E1 diet compared with those fed the casein or Soy-IF diets. Mice fed Soy+NSoy had a lower tumor incidence than mice fed casein, but not Soy-IF. Genistein did not affect tumor incidence. Soy protein, independently of phytoestrogens or E1, significantly reduced relative colon weight, tumor burden and multiplicity. Relative colon weight was lower (P=0.008) in mice fed Soy+E1 than in the other soy-fed groups. Tumor incidence in this group was lower than in the casein and soy-IF-fed groups and tended to be lower than in the others (P=0.020). Hence, soy protein and NSoy protect mice from colon cancer, and E1 further reduces colon tumorigenesis in mice, independently of ERalpha.
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PMID:Dietary soy isoflavones and estrone protect ovariectomized ERalphaKO and wild-type mice from carcinogen-induced colon cancer. 1470 14

Azoxymethane (AOM) is claimed to be a colon-specific carcinogen. In our studies, AOM was administered to adult BDIX/OrlIco rats by four weekly subcutaneous injections of 15 mg/kg body weight each - two periods of 2 weeks of AOM treatment separated by a one-week break. This treatment schedule resulted in colon carcinomas with a high frequency (75-100%) and with a high reproducibility. However, some serious side effects are associated with this carcinogen treatment. In addition to the colorectal tumours, we found small intestinal tumours, hepatic lesions and a high frequency of mesenchymal renal tumours which increased with longer latency periods. The renal tumours were only found in female rats, and this indicates a possible relation to sex hormones. We therefore analyzed both male and female kidneys for the expression of estrogen and progesterone receptors by immunohistochemical methods. A positive nuclear reaction for estrogen receptor was present in most tumour cells in all tumours and occasionally in nuclei of entrapped tubular cells, but never in glomeruli. Normal appearing renal tissue from female rats showed no positive reaction, but in male rats a slight nuclear reaction was seen in tubuli in the peripheral part of the medulla. A similar pattern was seen for progesterone receptors, but less pronounced. No rats developed tumours in the external ear canal, which is in contrast to studies performed in other rat strains. This may therefore be strain related. In order to reduce the secondary effects of the induction of colon cancer by AOM, it is advisable to use male rats only and a maximum latency period of 32 weeks.
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PMID:Secondary effects induced by the colon carcinogen azoxymethane in BDIX rats. 1551 Dec 68

We have known for many years that estrogen is more than the female hormone. It is essential in the male gonads, and in both sexes, estrogen has functions in the skeleton and central nervous system, on behavior, and in the cardiovascular and immune systems. An important aspect of the discovery of estrogen receptor (ER) beta is that the diverse functions of estrogen can now be divided into those mediated by ERalpha and those mediated by ERbeta. Pharmacological exploitation of this division of the labors of estrogen is facilitated by the ligand-binding specificity and selective tissue distribution of the two ERs. Because the ligand binding domains of ERalpha and ERbeta are significantly different from each other, selective ligands can be (and have been) developed to target the estrogenic pathway that is malfunctioning, without interfering with the other estrogen-regulated pathways. Because of the absence of ERbeta from the adult pituitary and endometrium, ERbeta agonists can be used to target ERbeta with no risk of adverse effects from chemical castration and uterine cancer. Some of the diseases in which there is hope that ERbeta agonists will be of benefit are prostate cancer, autoimmune diseases, colon cancer, malignancies of the immune system, and neurodegeneration.
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PMID:Reflections on the discovery and significance of estrogen receptor beta. 1585 73

We investigated the clinicopathologic and oncoprotein expression characteristics of 11 pure mucinous and 76 non-mucinous infiltrating ductal carcinomas in the human female breast. We compared patient age, tumor size, axillary lymph node status, and the expression of estrogen receptor (ER), progesterone receptor (PR), deleted-in-colon cancer (DCC), HER-2/neu, and p53. Mucinous carcinoma with axillary lymph node metastasis occurs less frequently than non-mucinous carcinoma (0% vs 63.1%; p = 0.0018). Compared with the non-mucinous type, mucinous carcinoma specimens have more DCC expression (100% vs 48.7%; p = 0.0027) and more ER expression (90.9% vs 26.9%; p = 0.0023), but less HER-2/neu overexpression (0% vs 38.1%; p = 0.0302). We confirmed that mucinous carcinoma samples from the breast reveal distinct clinicopathologic and oncoprotein expression features compared with non-mucinous carcinoma and, therefore, it seems reasonable to suggest different biologic characteristics and manifestations.
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PMID:Expression of p53, DCC, and HER-2/neu in mucinous carcinoma of the breast. 1596 65

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11

Polyamines and their rate-limiting enzyme, ornithine decarboxylase (ODC), are actively involved in cell growth and differentiation. The phytoestrogen genistein has been demonstrated to possess antitumor properties by influencing proliferation, differentiation, and apoptosis. The aim of this study was to investigate the effects of genistein at concentrations ranging from 0.01 to 100 microM on the polyamine biosynthesis, cell proliferation, and apoptosis in the estrogen receptor-positive DLD-1 human colon cancer cell line. Polyamine levels and ODC activity were evaluated by high performance liquid chromatography and radiometric technique, respectively. The proliferative response was estimated by [3H]-thymidine incorporation and the colorimetric 3-(4,5 di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Apoptosis was investigated by DNA fragmentation. Bax and Bcl-2 gene expressions were evaluated by multiplex-polymerase chain reaction. At concentration >or=1 microM, genistein decreased significantly the ODC activity and the polyamine levels. At the same concentration, genistein also increased significantly Bax mRNA expression, but not Bcl-2 mRNA expression. Higher concentrations (>or=10 microM) were needed to obtain a significant inhibition of cell proliferation and DNA fragmentation. The results of this study suggest that genistein can affect growth of DLD-1 cells by both decreasing polyamine biosynthesis and inducing apoptosis. However, further studies are required to assess the true ability of a soy rich diet in modifying colon cancer risk.
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PMID:Effects of genistein on the polyamine metabolism and cell growth in DLD-1 human colon cancer cells. 1609 Oct 8

Approximately 30-40% of estrogen receptor alpha (ERalpha)-positive breast tumors express high levels of the cyclooxygenase-2 (COX-2) protein, and these high levels have been associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce drug resistance in ERalpha-positive breast tumors, thus reducing the survival rate of patients with such tumors. Human breast cancer cell lines that express high levels of COX-2 are generally ERalpha negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ERalpha-positive MCF-7 human breast cancer cells (MCF-7/COX-2). MCF-7/COX-2 cells were resistant to the selective estrogen receptor modulator tamoxifen but not to its analog, raloxifene. MCF-7/COX-2 cells were also resistant to the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) but not to its analog, all-trans retinoic acid. In contrast, the sensitivities of MCF-7/COX-2 cells to doxorubicin and paclitaxel were similar to those of the parental MCF-7 cells. We then determined which COX-2 product, prostaglandin E2 (PGE2) or prostaglandin F2alpha is involved in the COX-2-mediated drug resistance. PGE2, but not PGF2alpha, blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE2 receptors and their downstream kinase effectors, protein kinases A and C, also blocked the growth inhibitory effects of these drugs. Increased levels of Bcl-2 and Bcl-XL proteins have been reported in mammary tumors of COX-2 transgenic mice and in human colon cancer cell lines that have high levels of COX-2. However, we did not observe any changes in Bcl-2, Bcl-XL, or Bax expression induced by COX-2 or PGE2. Here we report the novel findings that COX-2 uses PGE2 to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ERalpha-positive breast cancer cells.
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PMID:Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells. 1612 22

Estrogen replacement therapy is associated with a reduced risk of colon cancer. Therefore, we evaluated the following ten estrogen metabolism-associated single-nucleotide polymorphisms (SNPs) by sequencing-on-chip technology using solid-phase polymerase chain reaction (PCR) on oligonucleotide microarrays: catechol-O-methyltransferase (COMT) Val158Met G-->A, 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17) vlV A-->C, cytochrome P-450 (CYP) 17 A2 allele T-->C, CYP1A1 MspI RFLP T-->C, CYP1A1 Ile462Val A-->G, CYP19 Arg264Cys C-->T, CYP19 C1558T C-->T, CYP 1B1 Leu432Val, CYP1B1 Asn453Ser, and estrogen receptor (ER) alpha IVS1 -401-->C in 76 patients with a family history of colon cancer and 722 healthy controls. Using stepwise logistic regression models, we found that none of the investigated SNPs is associated with a family history of colon cancer in a univariate and multivariate logistic regression model. In addition, when all two-way interactions of the investigated SNPs were ascertained, no significant interactions between SNPs were observed. In conclusion, we found no association between the carriage of one or multiple SNPs of the estrogen metabolism and a family history of colon cancer.
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PMID:Ten polymorphisms of estrogen-metabolizing genes and a family history of colon cancer--an association study of multiple gene-gene interactions. 1620 20

Estrogen and androgens are thought to be involved in the etiology of colorectal cancer. We evaluate genetic variants of the estrogen receptor genes (ERalpha and ERbeta) and the androgen receptor gene (AR). We use data from two large case-control studies of colon (n = 1,580 cases and 1,968 controls) and rectal (n = 797 cases and 1,016 controls) cancer. We evaluated the 351A >G XbaI polymorphism of ERalpha, the 1,082 G >A and CA repeat polymorphisms of ERbeta, and the CAG repeat of AR. Having two 25 or more CA repeats in ERbeta was associated with an increased relative risk of colon cancer in women [odds ratio (OR), 2.13; 95% confidence interval (95% CI), 1.24-3.64] but not in men (P(interaction) relative excess risk from interaction < 0.01; multiplicative = 0.03). Increasing number of AR CAG repeats was directly associated with colon cancer among men (OR, 1.28; 95% CI, 1.06-1.54), but not women (OR, 0.83; 95% CI, 0.68-1.02); the interaction P value for AR gene x sex was <0.01. Taking hormone replacement therapy (HRT) was associated with a reduced risk of colon cancer in the presence of the R allele of the ERbeta gene, whereas an R allele was associated with increased risk among postmenopausal women who did not take HRT. Postmenopausal women not using HRT who had > or =25 CA repeats of the ERbeta gene had over a 6-fold increased risk of colon cancer (OR, 6.71; 95% CI, 2.89-15.6). Our results suggest that the ERbeta gene is more important than ERalpha in the etiology of colorectal cancer.
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PMID:Associations between ERalpha, ERbeta, and AR genotypes and colon and rectal cancer. 1636 13

The gene that encodes the alpha-isoform of phosphatidylinositol 3-kinase (PIK3Ca) is frequently mutated in human cancers. We profiled the mutation status of the PIK3Ca gene in the National Cancer Institute (NCI)-60 panel of human cancer cell lines maintained by the Developmental Therapeutics Program of the NCI. Mutation hotspots on the gene were PCR amplified and sequenced, and the trace data were analyzed with software designed to detect mutations. Seven of the cell lines tested have PIK3Ca mutations: two lines derived from breast cancer, two from colon cancer, two from ovarian cancer, and one from lung cancer. BRAF and EGFR genes were normal in the PIK3Ca mutant lines. Two of the cell lines with mutant PIK3Ca also have a mutant version of the KRAS gene. The mutation status was correlated with array-based gene expression that is publicly available for the NCI-60 cell lines. We found increased expression levels for estrogen receptor (ER) and ERBB2 in PIK3Ca mutant lines. The PIK3Ca mutation status was also correlated with compound screening data for the cell lines. PIK3Ca-mutant cell lines were relatively more sensitive than PIK3Ca-normal cell lines to the ER inhibitor tamoxifen and the AKT inhibitor triciribine, among other compounds. The results provide insights into the role of mutant PIK3Ca in oncogenic signaling and allow preliminary identification of novel targets for therapeutic intervention in cancers harboring PIK3Ca mutations.
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PMID:Correlation of PIK3Ca mutations with gene expression and drug sensitivity in NCI-60 cell lines. 1637 1


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