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)

We previously reported that the expression on the primary tumour of the antigen CaMBr8 was related to a short survival, attributable either to higher tumour aggressiveness or a poor response to oophorectomy. To further verify the CaMBr8 prognostic value, we analysed retrospectively 862 breast cancer patients with a 19 year follow-up. In this series, CaMBr8 expression was found to be associated to some negative prognostic factors (premenopausal status, lymphnode invasion, a high number of mitosis and HER-2/neu oncoprotein expression), but had no influence on the patients' survival. Direct association with a poor prognosis was only evident in patients with lobular or mixed breast carcinoma, which however represent only a small fraction of the total breast cancers. Another possibility was that CaMBr8 could identify a subgroup of patients which did not respond to hormone therapy. To verify this hypothesis we evaluated on a second series of 116 patients the relationship between CaMBr8 expression and hormone-receptor levels. A negative association emerged which was also observed in vitro in the human breast cancer line MCF-7 treated with Sodium Butyrate, a differentiation inducer, which reduced hormone-receptor levels and increased CaMBr8 expression. In conclusion, the longer survival of CaMBr8 negative tumour patients observed in the initial study, was probably related to a better response to oophorectomy, due to the hormone-receptor level of their tumours.
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PMID:Study of the biological and prognostic significance of the antigen CaMBr8 on breast carcinoma. 155 5

We have previously defined a human mammary epithelial antigen using a murine monoclonal antibody (MAb), designated DF3, prepared against a membrane-enriched fraction of a human breast carcinoma. MAb DF3 detects a cell surface antigen with a molecular weight (mw) of approximately 300 Kd and a higher mw species also detectable in human milk. These findings and the demonstration that butyric acid (BA) increases DF3 antigen expression suggested that MAb DF3 reacts with a differentiation antigen detectable in human breast carcinoma cells. The results of the present study demonstrate that MAb DF3 reacts with two mucin-like high mw glycoproteins (330 and 450 Kd) present in MCF-7 breast carcinoma cells. The results also demonstrate that the intracellular content and secretion of DF3 antigen is increased by 12-O-tetradecanoylphorbol-13-acetate (TPA) and 1-beta-D-arabinofuranosylcytosine (ara-C). Other known inducers of differentiation including retinoic acid (RA), hexamethylene bisacetamide (HMBA), 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) and certain polar solvents decrease DF3 antigen expression. Furthermore, the results demonstrate that DF3 antigen is secreted and that the extent coincides with changes in intracellular content. Finally, actinomycin D and cycloheximide inhibit the increases in DF3 antigen expression following TPA treatment thus suggesting that newly synthesized RNA and protein are required for induction of this antigen. Thus, the monitoring of DF3 antigen expression may provide a marker for studying maturation of human breast cancer cells.
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PMID:Effects of maturational agents on expression and secretion of two partially characterized high molecular weight milk-related glycoproteins in MCF-7 breast carcinoma cells. 241 36

Butyrate has been proposed as an antineoplastic agent, leading to the inhibition of tumorigenesis. The purpose of this study was to examine butyrate, supplied as tributyrin (Tbn) or as a natural component of anhydrous milk fat (AMF), on the development of nitrosomethylurea-induced mammary tumors in female Sprague-Dawley rats. Diets were 1) semipurified rodent diet (AIN-93) with high fat [20% sunflower seed oil (SSO), control], 2) SSO diet with Tbn added at 1%, 3) SSO diet with Tbn added at 3%, and 4) 19% AMF with 1% SSO diet, which contained butyrate equivalent to the 1% Tbn diet. These diets were fed ad libitum from weaning at 21 days of age, and at 24 days of age each rat was injected with nitrosomethylurea (50 mg/kg body wt i.p.). At any one period, there was a relative risk increase of 88% (p < 0.05) that rats in the SSO diet group would develop a mammary tumor compared with those in the AMF diet group. The addition of 1% and 3% Tbn to SSO diets reduced the tumor incidence by 20% and 52%, respectively, in comparison to SSO alone (p < 0.05). There was a linear inverse relationship between Tbn concentration and rats developing a tumor. From 89 days to the end of the experiment, rats fed the diet containing 3% Tbn showed a significantly lower multiplicity of palpable tumors (50% less at Day 118, p < 0.05) than SSO-fed rats. These results indicate that although the AMF diet was effective, particularly early in reducing mammary tumorigenesis, the 3% Tbn diet produced a sustained reduction of tumor multiplicity relative to the control (SSO) group. An inhibitory influence of butyrate on mammary tumorigenesis against a background of high polyunsaturated fat diet has been demonstrated in this animal model of breast cancer.
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PMID:Dietary butyrate inhibits NMU-induced mammary cancer in rats. 1089 33

Dual specificity protein phosphatases (DSPases) are key regulators of signal transduction, oncogenesis and the cell cycle. Few potent or specific inhibitors of DSPases, however, are readily available for these pharmacological targets. We have used a combinatorial/parallel synthetic approach to rigidify the variable core region and modify the side chains of 4-(benzyl-(2-[2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)- 2-decanoylamino butyric acid (or SC-alphaalphadelta9), which is the most active element in a previously described library of phosphatase inhibitors (Rice, R. L.; Rusnak, J. M.; Yokokawa, F.; Yokokawa, S.; Messner, D. J.; Boynton, A. L.; Wipf, P.; Lazo, J. S. Biochemistry 1997, 36, 15965). Several analogues were identified as effective inhibitors of the protein tyrosine phosphatase (PTPase) PTP1B and the DSPases VHR and Cdc25B2. Two compounds, FY3-alphaalpha09 and FY21-alphaalpha09, were partial competitive inhibitors of Cdc25B2 with Ki values of 7.6+/-0.5 and 1.6+/-0.2 microM, respectively. FY21-alphaalpha09 possessed only moderate activity against PTP1B. Consistent with its in vitro anti-phosphatase activity, FY21-alphaalpha09 inhibited growth in MDA-MB-231 and MCF-7 human breast cancer cell lines. FY21-alphaalpha09 also inhibited the G2/M transition in tsFT210 cells, consistent with Cdc25B inhibition. Several architectural requirements for DSPase inhibition were revealed through modification of the side chain moieties or variable core region of the pharmacophore, which resulted in decreased compound potency. The structure of FY21-alphaalpha09 provides a useful platform from which additional potent and more highly selective phosphatase inhibitors might be generated.
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PMID:Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array. 1089 22

Full-term pregnancy early in reproductive life is protective against breast cancer in women. The protective effects of parity have variously been attributed to the differentiation that accompanies pregnancy and lactation, alterations in ovarian hormone receptor levels, and altered sensitivity to ovarian hormones. Butyrate, a short-chain fatty acid, induces differentiation in breast cancer cell lines and decreases hormone receptor expression. Butyrate also inhibits proliferation in breast cancer cell lines and modulates expression of key cell cycle-regulatory proteins including cyclin D1. Given these properties, butyrate could be considered a promising agent for breast cancer prevention. Therefore, this study aimed to determine the effects of butyrate on normal human breast epithelial cells and to compare the effects of two stable butyrate derivatives with more favorable pharmacological properties: phenylacetate and its p.o. active precursor phenylbutyrate. Treatment with each agent resulted in concentration-dependent growth inhibition in a normal breast epithelial cell line and two breast cancer cell lines (MCF-7 and MDA-MB-231). Phenylbutyrate and butyrate inhibited proliferation to a similar extent, but phenylacetate was less effective in all of the cell lines. All three of the agents induced differentiation (accumulation of lipid droplets) in normal as well as in breast cancer cells and caused a decrease in estrogen receptor (ER) mRNA in MCF-7 cells. The butyrates decreased expression of cyclin D1, increased expression of p21(Waf1/Cip1), and hypophosphorylated pRB in the normal mammary epithelial cells. The effects on cyclin D1 expression correlated with the effects on cell proliferation, which suggests that modulation of cyclin D1 expression may underpin the antiproliferative effects of butyrates. We have shown that butyrate and butyrate-like agents are able to decrease proliferation and induce differentiation in normal breast cells as well as in malignant breast cells (ER-positive and ER-negative) and, as such, may be considered as candidate chemopreventative agents for women at high risk of developing breast cancer.
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PMID:Histone deacetylase inhibitors decrease proliferation and modulate cell cycle gene expression in normal mammary epithelial cells. 1110 51

1. This study was performed to determine the effect and action mechanisms of sodium butyrate (NaB) on the growth of breast cancer cells. 2. Butyrate inhibited the growth of all breast cancer cell lines analysed. It induced cell cycle arrest in G1 and apoptosis in MCF-7, MCF-7ras, T47-D, and BT-20 cells, as well as arrest in G2/M in MDA-MB-231 cells. 3. Transient transfection of MCF-7 and T47-D cells with wild-type and antisense p53 did not modify butyrate-induced apoptosis. Pifithrin-alpha, which inhibits the transcriptional activity of P53, did not modify cell growth or apoptosis of MCF-7 and T47-D cells treated with butyrate. These results indicate that P53 was not involved in butyrate-induced growth inhibition of breast cancer cells. 4. Treatment of MCF-7 cells with anti-Fas agonist antibody induced cell death, indicating that Fas was functional in these cells. Moreover, butyrate potentiated Fas-induced apoptosis, as massive apoptosis was observed rapidly when MCF-7 cells were treated with butyrate and anti-Fas agonist antibody. In addition, butyrate-induced apoptosis in MCF-7 cells was considerably reduced by anti-Fas antagonist antibody. Western blot analysis showed that butyrate increased Fas and Fas ligand levels (Fas L), indicating that butyrate-induced apoptosis may be mediated by Fas signalling. 5. These results demonstrate that butyrate inhibited the growth of breast cancer cells in a P53-independent manner. Moreover, it induced apoptosis via the Fas/Fas L system and potentiated Fas-triggered apoptosis in MCF-7 cells. These findings may open interesting perspectives in human breast cancer treatment strategy.
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PMID:Sodium butyrate induces P53-independent, Fas-mediated apoptosis in MCF-7 human breast cancer cells. 1178 82

Previously we identified 4-[1-(4-hydroxyphenyl)-2-phenylbuten-1-yl]phenoxy-n-butyric acid (4HBA) and its des-hydroxy analog (BA) as potential selective estrogen receptor modulators (SERMs) in the ovariectomized (OVX) rat. The aim of the present study was to characterize comprehensively the effects of 4HBA and BA in both the OVX rat and in estrogen-responsive cells. Thus, 4HBA was found to be an estrogen antagonist with partial agonist efficacy in estrogen-responsive reporter gene and estrogen-dependent proliferation assays (MVLN cells and MCF-7 human breast cancer cells, respectively). In the OVX rat, 4HBA and BA were equally effective and comparable to other known SERMs regarding (a) serum cholesterol reduction and suppression of serum markers of excessive bone metabolism, and (b) partial agonist efficacy in reproductive tissue relative to steroidal estrogens. Like steroidal estrogens, both compounds increased serum triglyceride levels, with BA being more effective in this regard. The maximal effects of 4HBA on all of these parameters except cholesterol lowering were seen at oral doses of 0.4 micromol/kg/day; maximal cholesterol lowering required doses of 10 micromol/kg/day. In OVX rat liver 9S fraction, BA was found to be efficiently converted to a single hydroxylated metabolite, 4HBA. These results suggest that the effects of BA in the OVX rat might, in part, be a consequence of biotransformation to 4HBA, and that those of 4HBA and BA in the OVX rat and in estrogen-responsive cells are qualitatively similar to those of SERMs such as tamoxifen and raloxifene.
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PMID:Characterization of selective estrogen receptor modulator (SERM) activity in two triarylethylene oxybutyric acids. 1199 94

In addition to its action as a topoisomerase II poison, mitoxantrone is activated by formaldehyde to bind DNA, forming DNA-adducts specifically at 5'CpG and CpA sequences, with an enhancement of adducts at methylated CpG sites. The butyric acid prodrug, AN-9 (pivaloyloxymethyl butyrate), releases formaldehyde upon cellular hydrolysis and our previous studies have shown that mitoxantrone acts synergistically with AN-9 in cytotoxicity assays. In this paper, we investigated the impact of methylation levels in the cell on mitoxantrone-induced cytotoxicity using the colon cancer cell line HCT116 and its derived DNA methyltransferase (DNMT) 1 and DNMT 3a knockout (DKO8) cell line. We found that decreased methylation levels in the DNMT-null cells led to at least a 2-fold reduction in mitoxantrone-induced cytotoxicity. Next, we studied the impact of mitox-antrone alone, and in combination with AN-9, on hypermethylated genes and their mRNA expression in breast cancer cells. Using methylation-specific PCR and RT-PCR, we found that mitoxantrone treatment of breast cancer cell lines resulted in demethylation of the 14.3.3s, Cyclin D2 and ERa genes, followed by re-expression of their mRNA. The effect of mitoxantrone on re-expression of key genes involved in cell cycle regulation, and ensuing death of the cells may be an additional, previously undiscovered mechanism of action of mitoxantrone.
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PMID:Mitoxantrone mediates demethylation and reexpression of cyclin d2, estrogen receptor and 14.3.3sigma in breast cancer cells. 1287 62

It has been suggested in some reports that dairy product consumption may increase the risk of breast cancer. This review gives a brief overview of the etiology of breast cancer and in particular the roles of fat, bovine growth hormone, insulin-like growth factor-1 and estrogens. Evidence from animal studies and epidemiology does not support a role for fat in the etiology of breast cancer. The daily intake of insulin-like growth factor-1 and biologically active estrogens from dairy products is minute in comparison to the daily endogenous secretion of these factors in women, whereas bovine growth hormone is biologically inactive in humans. On the other hand, milk contains rumenic acid, vaccenic acid, branched chain fatty acids, butyric acid, cysteine-rich whey proteins, calcium and vitamin D; components, which have the potential to help prevent breast cancer. Evidence from more than 40 case-control studies and 12 cohort studies does not support an association between dairy product consumption and the risk of breast cancer.
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PMID:Dairy product consumption and the risk of breast cancer. 1637 55

Butyrate, a short chain fatty acid, exhibits a wide variety of biological effects including the inhibition of cell growth, change of cellular morphology and the induction of apoptosis. Sodium butyrate-induced apoptosis has been reported to associate with the up-regulation of pro-apoptotic Bax expression, and the down-regulation of anti-apoptotic Bcl-2 and Bcl-XL expressions. However, in some cases, butyrate has also been shown to cause apoptosis without change in Bcl-2, Bcl-XL and/or Bax. This study investigates the detailed mechanisms of sodium butyrate-induced apoptosis. The effect of sodium butyrate was analyzed in the induction of caspase activities, formation of caspase active forms and mRNA levels in human breast cancer cell line MRK-nu-1. Induction of activities of caspase-3, -10 and, to some extent, -8 and formation of DNA fragmentation were observed with sodium butyrate in a dose- and/or time-dependent manner. The levels of caspase-10 mRNA expression markedly increased in a time-dependent manner by the treatment of sodium butyrate, whereas caspase-8 mRNA expression was not changed. Inhibitors of caspase-8 and caspase-10 reduced caspase-3 activity and subsequent DNA fragmentation induced by sodium butyrate. These caspase inhibitors also inhibited the cleavage of pro-caspase-3 to the active forms indicated by Western blotting analysis. Pyrrolidine dithiocarbamate also inhibited the induction of caspase-10 mRNA expression and caspase-3 activation. Contrary to other reports, levels of Bcl-2, Bcl-XL and Bax mRNA expressions were not distinctly changed by even 5 mM sodium butyrate treatment. Our results suggest that sodium butyrate may trigger apoptosis via the induction of the caspase-10 expression.
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PMID:The important role of caspase-10 in sodium butyrate-induced apoptosis. 1820 3


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