Article

Estrogenic and DNA-Damaging Activity of Red No. 3 in Human Breast Cancer Cells

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Abstract

Exposure to pesticides, dyes, and pollutants that mimic the growth promoting effects of estrogen may cause breast cancer. The pesticide DDT and the food colorant Red No. 3 were found to increase the growth of HTB 133 but not estrogen receptor (ER) negative human breast cells (HTB 125) or rat liver epithelial cells (RLE). Red No. 3, beta-estradiol, and DDT increase ER site-specific DNA binding to the estrogen response element in HTB 133 cells and increase cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells. Site-specific DNA binding by p53 in RLE, HTB 125, HTB 133, and MCF-7 cells was increased when they were treated with Red No. 3, which suggests that cellular DNA was damaged by this colorant. Red No. 3 increased binding of the ER from MCF-7 cells to the estrogen-responsive element. Consumption of Red No. 3, which has estrogenlike growth stimulatory properties and may be genotoxic, could be a significant risk factor in human breast carcinogenesis.

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... There has been an increasing concern among the general and medical community in relation to the potential environmental hazard that estrogens present to health in general, although the mechanisms by which they affect homeostasis are still barely known123. It has been known for several years that exposure to some xenohormones increases the production of reactive oxygen species, which in turn could inflict structural damage to cell DNA of target organs, as well as to DNA from other systemic cells [4,5]. The genotoxic action of contaminating agents affects human health directly, damaging the genetic material, which is considered to play an important role in oncogenesis [6,7]. ...
... Xenohormones can have a bi-functional behavior, depending on their mechanism of action, either through a genetic or hormonal route; this depends on their structure, concentration and exposure period [4]. On the other hand, it has been reported that exposure to some xenoestrogens and to estrogenic metabolites promotes the production of free radicals through the hydrogen peroxide (H 2 O 2 ) reduction cycle, by means of the P 450 oxidase and reductase enzymes, giving origin to the production of oxygen reactive species which might damage the genetic material [33]. ...
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The genotoxicity of some environmental contaminants may affect human health directly by damaging genetic material and thus plays an important role in cancer development. Xenoestrogens are one kind of environmental pollutants that may alter hormonal routes or directly affect DNA. The number of available biomarkers used to assess genetic risk and cancer is very extensive. The present study evaluated genotoxicity produced by the pesticide DDT on systemic and mammary gland cells obtained from adult female Wistar rats. Oral mucosa cells micronuclei were assessed; the comet assay in peripheral blood-isolated lymphocytes and mammary epithelial cells was also carried out. Additionally, oxidative stress was studied in mammary tissue through a lipid peroxidation assay. Our data showed an increase in lipid peroxidation, product of an increase in free oxygen radical levels, which leads to an oxidative stress status. Our results suggest that DDT is genotoxic, not only for lymphocytes but also to mammary epithelial cells.
... Tsuda et al. (2001) observed colon DNA damage associated with intake of three azo dyes, amaranth (Red 2), allura red (Red 40) and acid red. Dees et al. (1997) reported that Red No. 3, which has estrogen like growth stimulatory properties, could be a significant risk factor in human breast carcinogenesis. ...
... To elucidate how estrogenic compounds can compete with DDT by their estrogenic potential (108,109) some studies have yielded several molecular mechanisms explaining this interaction. For instance, it has been shown that DTT increased the growth of HTB 133 cells by enhancing the ER-DNA specific binding to the specific ERE (estrogen response elements) and also potentiates the activity of cyclin-dependent kinase 2 in MCF-7 breast cancer cells but not ER-negative HTB 125 breast cells or rat liver epithelial cells (110). Besides, there is evidence in vivo and in vitro that shows the influence of DTT in the interaction of ER and specific genes promoting cell proliferation (11,109), in fact, DTT can also bind to ERs in different places of the body other than female reproductive sites. ...
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... But few studies have focused on the estrogenic activity of food dyes. Studies concern mainly food colors such as tartazine (E 102), sudan I and erythrosine B (E 127) which have effects on the chromosomal structure and can increase Estrogen Receptor (ER) site-specific DNA binding effect to Estrogen Response Element (ERE) in HTB 133 cells [12,13] and in the E-screen test [14]. Axon et al. [15] helped to identify several modulator of the human ER among food additives such as tartazine and sunset yellow. ...
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... • Kamel 2011 • Gao 2011 • Shimada 2010 • Amin 2010 • Hashem 2010 • Moutinho 2007 • Lau 2006 • Murphy 2006 • Ashida 2000 • Aboel • Aoshima 1997 • Dees 1997 • Reyes 1996 • Voorhees 1983 • Tanaka 1993Tanaka , (1980 and Lafferman and Silbergeld (1979) are all but ignored by the reviewers. ...
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This article reviews the effects of Endocrine Disrupters (EDs) on cancer incidence in humans, the analysis being practically restricted to the influence of xenoestrogens on the occurrence of breast cancer. Although receptor-mediated mechanisms play an important role in eliciting the effects of (xeno)oestrogens (XEs), it should not be overlooked that other pathways exist, and that any evaluation must therefore consist of the net result of all influences. It is not acceptable to base the evaluation of the effects of xenoestrogens, or their inclusion in the category of EDs, solely on their property to bind the oestrogen receptor (ER). Other mechanisms contribute in eliciting the oestrogenic response and are briefly reviewed. They include serum factors; the binding to carrier proteins; alterations in metabolic pathways; interactions between oestrogens; growth factors and their receptors and oncogenes; disturbances in signal transduction pathways and interference with several accessory mechanisms of carcinogenesis. The particular carcinogenesis mechanisms underlying the action of (xeno)oestrogens are discussed. This mechanism implicates the absence of any threshold and-consequently-inducing effects at the lowest possible concentrations: one molecule. Other factors influencing the effects of XEs are represented by the occurrence of a membrane oestrogen receptor, different from the traditional nuclear ER, participating in the regulation of Prolactin production by the hypophysis after stimulation of the hypothalamic-hypophyseal pathways. Strong co-operation also exists with thyroid hormones. Many epidemiological studies, of which some are critically reviewed, support the basic role of XEs as one of the causative factors of breast cancer. This only serves to underscore the compulsory application of the precautionary principle, once a compound has been proven to exert endocrine disrupting properties, and the necessity to evaluate all modes of action of EDs.
Article
We report here about the practice of using metanil yellow, a non permitted synthetic dye, in the adulteration of some food items produced by the organized and unorganized sectors located in different districts in West Bengal, India. We considered three food items- turmeric powder, ladoo and besan for the detection of the presence of metanil yellow. We observed that 58 of the 253 samples i.e. 20.94% of total samples contain metanil yellow in which 36.21% of the positive samples contained the metanil yellow below the maximum permissible limit i.e., below the 100 mg kg-1 food samples and 63.79% of the positive samples contained above the maximum permissible limit i.e., above the 100 mg kg-1 food samples as specified in the Prevention of Food Adulteration Act of India (PFA, 2008). We observed insignificant presence of metanil yellow in besan samples. We did not observe significant presence of metanil yellow in the same food samples collected from the organized sectors. We also found that all the positive samples i.e., the samples containing significant amount of metanil yellow were prepared from the food items collected from the unorganized sectors. From the study it is concluded that the unorganized sectors practice to use metanil yellow indiscriminately to adulterate the food items. We suggest strict governmental vigilance to prevent food adulteration with metanil yellow to avoid human health hazards.
Conference Paper
Acid Red 51, commonly named as Erythrosine B (Ery B), a water-soluble xanthene class of dye, is widely used in cosmetics, foodstuffs, medicines and textiles. Some procedures for textile wastewater remediation, such as photochemical and chemical degradation are not recommended mainly due to the formation of toxic by-products. Therefore, development of low-cost and efficient methods, such as sorption on agricultural waste is a good alternative. The present paper aims to investigate the removal of Ery B by sorption on agro-waste. Pumpkin seeds hull (PSH) has been chosen as a sorbent. Batch experiments were conducted for the study of the influence of some parameters on dye adsorption efficiency, such as: dye concentration (5 to 50 mg L-1), temperature (20, 30, 40, 50ºC) and the dosage of adsorbents (5 to 30 g L-1). Kinetic studies of Ery B adsorption on PSH were carried out at 25ºC, using aqueous solutions with 10, 20 and 30 mg L-1 of dye. All the experiments were conducted at the natural pH of the solution, 5.6. The results showed that the hazardous water-soluble dye Ery B can be efficiently removed from the aqueous solutions by adsorption over PSH. Using 20 g L-1 of PSH the amount of dye uptake was around 3.5 mg g-1. Adsorption has been correlated with the different adsorption isotherms and based on the data free energy of adsorption (ΔGº), enthalpy (ΔHº), and entropy (ΔSº) were calculated.
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Currently, natural food colorants and preservatives are being used for their general health benefits. Monascus koji, the product of certain fungi that grow on rice grains, has been added to many foods for coloring and preservation. In this study, the antimicrobial activities of Monascus koji ethanol extracts were investigated. Six Monascus strains (M. araneosus KFRI 00371, M. kaoliang ATCC 46597, M. pilosus IFO 4520, M. purpureus IFO 4482, M. ruber IFO 32318 and M. sp. ATCC 16437) were selected based on their relative intensity of red pigment. Two Monascus extracts, M. kaoliang ATCC 46597 and M. purpureus IFO 4482, displayed antimicrobial activities against Bacillus subtilis, B. cereus, Micrococcus luteus, Staphylococcus aureus and Salmonella typhimurium in concentration-dependent manners. The two extracts showed their strongest antimicrobial activity against S. typhimurium, a cause of food poisoning. Therefore, these results suggest that Monascus koji could be used as a natural food colorant and preservative.
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In this paper, the capacity of a soil to retain the dye Erythrosine B from aqueous solution by sorption has been studied. Batch adsorption experiments were conducted to investigate the sorption of the dye from aqueous solutions onto soil with particles of different size. Different models were used to describe the kinetic data, to calculate the corresponding rate constants and to predict the theoretical capacities of soil for dye sorption.
Article
Novel coated graphite electrode (CGE) for the determination of quinoline yellow (QY), an artificial food colorant, was evaluated based on the use of tetraphenylphosponium-QY ion-pair complex as the electroactive substance. The electrode revealed linear emf-pQY response over wide concentration ranges (1.0 × 10−1 ∼ 5.0 × 10−5 M) with a slope −30.1 ± 0.2 mV decade−1 and a limit of detection of 4.0 × 10−5 M. The electrode showed good stability, reproducibility and fast response (<5 s). It can be used in wide pH range (4.7–10.7) and was successfully applied to determination of quinoline yellow in artificial mixtures and commercial soft drinks. The results obtained with the electrode were in good agreement with the value obtained by using HPLC measurements, as an official method.
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Estrogen receptor (ER) transactivation assays were initially designed to study endogenous mechanisms of steroid hormone action, but more recently have been used to assess industrial chemicals for potential estrogenic activity. Given the diverse spectrum of physicochemical properties of these chemicals, we examined the effects of pH (a weak organic and strong inorganic acid and base), hyperosmolality (NaCl, mannitol) and two different vehicles (DMSO, Triton X-100) on responses to estradiol-17β (E2) in an ER transactivation assay. MCF-7 human breast cancer cells were transiently transfected with a chimeric estrogen receptor (Gal4-HEG0) and a Gal4-regulated luciferase reporter gene (17m5-G-Luc), treated with E2 under various test conditions, and then assessed for ER-mediated luciferase activity. Maximal E2-induced reporter activity was observed at pH 7.8 (pre-incubation), but was markedly reduced at pH ⩽7.5 or ⩾8.0 (P < 0.001), even though there was no evidence of cytotoxicity. Hyperosmolality induced by addition of mannitol (⩾25 mM) resulted in significant decreases in overall assay responsiveness, whereas NaCl (⩾80 mM) decreased the sensitivity of the assay by increasing the no-observed-effect level for E2 compared to control cultures (330 mOsm). The maximal DMSO concentration that resulted in consistently high E2-induced reporter activity was 0.1%, whereas concentrations of Triton X-100 above 1 ppm inhibited E2-induced reporter responses and were cytotoxic above 10 ppm. These results indicate that various physicochemical factors have the potential to confound assay data if not kept within predefined operational limits. Copyright © 2000 John Wiley & Sons, Ltd.
Article
In this research, the construction and general performance characteristics of a sunset yellow sensor based on sunset yellow-cetyl pyridinum (SY-CPY) ion pair as an ion exchanger were described. A coated platinum wire electrode (CPE) was prepared and compared with coated graphite (CGE) and membrane electrode (PME). The CPE exhibited a rapid and Nernstian response (-29.77 ± 0.2 mV decade-1) to SY concentration range from 3.16 × 10-7 to 3.16 × 10-3 mol dm-3 within pH 4.5-9.5. Interfering effects of some foreign substances were reported. The optimized matrix was successfully applied to the determination of SY in artificial mixtures and commercial soft drinks. The results showed good agreements with the determination made by use of high-performance liquid chromatography.
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Science remains an eminently social institution, though the interactions between science and society are often poorly understood. This article addresses the context of recent efforts to identify environmental contributions to cancer. The authors first examine cancer incidence and discuss how incidence patterns may be related to air pollution and occupational and general toxic chemical and xenestrogen exposures. They then discuss the social context in which cancer research and treatment occurs, including the dominating role of the biomedical model and socioeconomic factors, including regulatory strategies that address single chemicals, corporate conflicts of interest, and the manipulation of public opinion. Last, they consider the broad context out of which cancer arises and discuss the merits of applying the precautionary principle to sustainable social policies. Progress in reducing cancer may be fruitfully made by returning our attention to broad-scale factors such as those affecting the quality of air, water, workplace, household environments, and the global climate.
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In order to set up an accurate quality criteria for the Boraginaceae that have been traditionally used for medical purposes and food colorant, and to assess its viability as functional food ingredient, antioxidant tests were conducted on the wild and cultivated plants. Variety of indicators including total contents of phenol, DPPH, SOD-liked effect, hydroxy radical-scavenging effect, lecithin oxidation inhibitory effect, etc were analyzed. Wild and cultivated gromwell's total contents of phenol in their methanol extracts were 0.14% and 0.13%, while they were most active in ethyl acetate extracts and n-hexane extracts, respectively. values of methanol extract of the wild and cultivated plants were 794.41 /mL and 971.86 /mL, indicating that the wild plant is more responsive (p
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Aromatase, a key steroidogenic enzyme that catalyses the conversion of androgens to estrogens, present a target for endocrine disrupting chemicals. However, little is known about the effect of pollutants on aromatase enzymes. In this study, we first optimized a non-radioisotope aromatase assay using rat ovarian microsomes in vitro and measuring the estrone level with an enzyme-linked immunosorbent assay (EIA method). The sensitivity of the EIA method was about ten times as high as that of the radioisotope (RI) method. A significant positive correlation was indicated between EIA and RI method. We used this EIA assay system to investigate the effects of aromatase activity on 45 chemicals that had previously been reported to act as endocrine disruptors or to have the possibility of having such an effect. Six of the chemicals, rose bengal, erythrosine, phloxine, allura red, gallic acid, and tributyltin, inhibited aromatase activity. The inhibitory effect of rose bengal was the strongest (IC50=2.4 x 10(-8) M), and its strength of inhibition was about 100 times that of a known aromatase inhibitor, 4-hydroxy-androstenedione (IC50=2.6 x 10(-6) M) but was about 1/25 that of fadrazole (IC50=1.0 x 10(-9) M). It is thought that this EIA method would be useful for measuring the aromatase activity of microstructures.
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We investigated the accumulation of p53 proteins after heat stress and their association with HSP72/HSC73 using four human glioblastoma cell lines. Human glioblastoma cell lines U-87MG and A-172 exhibited no mutation in the region between the 2nd and 11th exons of the p53 gene, whereas A-7 and T98G had mutations in exon 5 and exon 7 of the p53 gene, respectively. In U-87MG and A-172, the levels of wild-type p53 protein were slightly increased by heat stress. Levels of mutant p53 protein were apparently increased by heat stress in A-7, but not in T98G. Furthermore, wild-type p53 proteins in both U-87MG and A-172 co-immunoprecipitated with antibody and HSP72 and HSC73 in them co-immunoprecipitated with anti-p53 antibody as did the mutant p53 proteins. These findings suggest that p53 proteins accumulated by heat stress are associated with HSP72 and HSC73.
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Extracts containing wild-type or mutant human estrogen receptor (ER) have been used to study the binding of ER to its responsive element (ERE). Estradiol (E2) or the antiestrogen hydroxytamoxifen is required for ER binding as assayed by gel retardation. The DNA binding domain (DBD) encompasses the highly conserved region C. Both intact ER-E2 complexes and ER mutants truncated for the hormone binding domain (HBD) bind as dimers to an ERE. However, an HBD-truncated ER binds less tightly to an ERE than an intact ER-E2 complex. The DBD and HBD contain a constitutive and a stronger ER-induced dimerization function, respectively. Thus, in addition to inducing the activation function associated with the HBD, estrogen plays a crucial role in the formation of stable ER dimers that bind tightly to ERE.
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Sewage, a complex mixture of organic and inorganic chemicals, is considered to be a major source of environmental pollution. A random screen of 20 organic man-made chemicals present in liquid effluents revealed that half appeared able to interact with the estradiol receptor. This was demonstrated by their ability to inhibit binding of 17 beta-estradiol to the fish estrogen receptor. Further studies, using mammalian estrogen screens in vitro, revealed that the two phthalate esters butylbenzyl phthalate (BBP) and di-n-butylphthalate (DBP) and a food antioxidant, butylated hydroxyanisole (BHA) were estrogenic; however, they were all less estrogenic than the environmental estrogen octylphenol. Phthalate esters, used in the production of various plastics (including PVC), are among the most common industrial chemicals. Their ubiquity in the environment and tendency to bioconcentrate in animal fat are well known. Neither BBP nor DBP were able to act as antagonists, indicating that, in the presence of endogenous estrogens, their overall effect would be cumulative. Recently, it has been suggested that environmental estrogens may be etiological agents in several human diseases, including disorders of the male reproductive tract and breast and testicular cancers. The current finding that some phthalate compounds and some food additives are weakly estrogenic in vitro, needs to be supported by further studies on their effects in vivo before any conclusions can be made regarding their possible role in the development of these conditions. Images Figure 1. Figure 2. Figure 3. Figure 4.
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It has been convincingly demonstrated that genotoxic stresses cause the accumulation of the tumor suppressor gene p53. One important consequence of increased p53 protein levels in response to DNA damage is the activation of a G1-phase cell cycle checkpoint. It has also been shown that G1-phase cell cycle checkpoints are activated in response to other stresses, such as lack of oxygen. Here we show that hypoxia and heat, agents that induce cellular stress primarily by inhibiting oxygen-dependent metabolism and denaturing proteins, respectively, also cause an increase in p53 protein levels. The p53 protein induced by heat is localized in the cytoplasm and forms a complex with the heat shock protein hsc70. The increase in nuclear p53 protein levels and DNA-binding activity and the induction of reporter gene constructs containing p53 binding sites following hypoxia occur in cells that are wild type for p53 but not in cells that possess mutant p53. However, unlike ionizing radiation, the accumulation of cells in G1 phase by hypoxia is not strictly dependent on wild-type p53 function. In addition, cells expressing the human papillomavirus E6 gene, which show increased degradation of p53 by ubiquitination and fail to accumulate p53 in response to DNA-damaging agents, do increase their p53 levels following heat and hypoxia. These results suggest that hypoxia is an example of a "nongenotoxic" stress which induces p53 activity by a different pathway than DNA-damaging agents.
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Exposure to estrogens during critical periods of development induces teratogenic and carcinogenic lesions in the reproductive tracts of humans and experimental animals. It is important to determine the molecular and cellular targets of estrogenic chemicals and to establish the mechanisms by which interactions of estrogens with the developing genital tract results in permanent lesions of growth and differentiation. The experiments presented here were designed to examined the effects of neonatal estrogen exposure on the expression of two genes, lactoferrin and epidermal growth factor, that are subject to steroid hormone regulation. Using in situ and Northern RNA hybridization, immunoblotting, and immunohistochemistry, our data demonstrate that exposure to the synthetic estrogen, diethylstilbestrol, during a critical neonatal period results in the persistent ovary-independent induction of mRNA and protein encoded by these two genes in the mouse uterus and vagina. The constitutive expression of lactoferrin and EGF, and probably other estrogen-regulated genes, may contribute to the establishment of a permanently "estrogenized" phenotype which is then instrumental in the development of abnormal tissue morphogenesis, function, and neoplasia in the rodent reproductive tract.
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Changes in documented risk factors for breast cancer and rates of screening cannot completely explain recent increases in incidence or mortality. Established risk factors for breast cancer, including genetics, account for at best 30% of cases. Most of these risk factors can be linked to total lifetime exposure to bioavailable estrogens. Experimental evidence reveals that compounds such as some chlorinated organics, polycyclic aromatic hydrocarbons (PAHs), triazine herbicides, and pharmaceuticals affect estrogen production and metabolism and thus function as xenoestrogens. Many of these xenoestrogenic compounds also experimentally induce mammary carcinogenesis. Recent epidemiologic studies have found that breast fat and serum lipids of women with breast cancer contain significantly elevated levels of some chlorinated organics compared with noncancer controls. As the proportion of inherited breast cancer in the population is small, most breast cancers are due to acquired mutations. Thus, the induction of breast cancer in the majority of cases stems from interactions between host factors, including genetics and environmental carcinogens. We hypothesize that substances such as xenoestrogens increase the risk of breast cancer by mechanisms which include interaction with breast-cancer susceptibility genes. A series of major epidemiologic studies need to be developed to evaluate this hypothesis, including studies of estrogen metabolism, the role of specific xenoestrogenic substances in breast cancer, and relevant genetic-environmental interactions. In addition, experimental studies are needed to evaluate biologic markers of suspect xenoestrogens and biologic markers of host susceptibility and identify pathways of estrogenicity that affect the development of breast cancer. If xenoestrogens do play a role in breast cancer, reductions in exposure will provide an opportunity for primary prevention of this growing disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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In mammalian cells inhibition of the cdc2 function results in arrest in the G2-phase of the cell cycle. Several cdc2-related gene products have been identified recently and it has been hypothesized that they control earlier cell cycle events. Here we have studied the relationship between activation of one of these cdc2 homologs, the cdk2 protein kinase, and the progression through the cell cycle in cultured human fibroblasts. We found that cdk2 was activated and specifically localized to the nucleus during S phase and G2. Microinjection of affinity-purified anti-cdk2 antibodies but not of affinity-purified anti-cdc2 antibodies, during G1, inhibited entry into S phase. The specificity of these effects was demonstrated by the fact that a plasmid-driven cdk2 overexpression counteracted the inhibition. These results demonstrate that the cdk2 protein kinase is involved in the activation of DNA synthesis.
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We have investigated the effect of chemotherapeutic and DNA damaging agents on binding of the tumor suppressor phosphoprotein p53 to its consensus DNA sequence. Activation of p53-DNA binding was seen for treatment with radiation, hydrogen peroxide, actinomycin D, Adriamycin, etoposide, camptothecin, 5-fluorouracil, mitomycin C, and cisplatin. These results showed that DNA strand breaks were sufficient to lead to increased levels of p53. The protein synthesis inhibitor cycloheximide blocks the increase in p53 following DNA damage. The increase in p53 activation in camptothecin treated cells may result, at least in part, from an increased half-life of the protein and consequent increases in intracellular protein concentration.
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The estrogen receptor (ER) can be activated as a transcription factor either by binding of cognate estrogenic ligand or, indirectly, by a variety of other extracellular signals. As a first step towards elucidating the mechanism of 'steroid-independent activation' of the ER by the epidermal growth factor (EGF), we have mapped the ER target domain and determined the signaling pathway. We show that the N-terminal transcriptional activation function AF-1, but not the C-terminal AF-2, is necessary for the EGF response. Both the EGF-induced hyperphosphorylation and the transcriptional activation of the unliganded ER depend on a phosphorylatable serine residue at position 118. However, its phosphorylation is not sufficient and, hence, there must be other target domains or proteins which fulfill an additional requirement for EGF signaling through the ER. Using dominant-negative Ras and MAP kinase kinase (MAPK kinase) and constitutively active MAPK kinase mutants, we show that EGF activates the ER by signaling through the MAPK pathway suggesting that MAPK directly phosphorylates the critical serine 118. Our results also imply that the steroid-independent activation of a variety of ER mutants, which arise during the malignant progression of breast tumors, may contribute to tamoxifen resistance.
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Cyclin-dependent kinases (Cdk) act to regulate G1- to S-phase transition in mammalian cells. We have studied the effects of estradiol and the steroidal antiestrogen ICI 182, 780 on induction of Cdk activity and the consequent phosphorylation of retinoblastoma protein (Rb) in estrogen-responsive MCF-7 breast cancer cells. Treatment of growth-arrested MCF-7 cells with physiological concentrations of estradiol led to a time-dependent increase in Cdk2-associated and cyclin E-dependent kinase activity, which was accompanied by hyperphosphorylation of Rb and S-phase entry. Induction of both Cdk2 activity and DNA synthesis by estradiol was dose dependent and was inhibited by coadministration of ICI 182,780. Elicitation of Cdk2 activity was found to require prolonged (> 8h) estradiol exposure. Levels of cyclins E and A were unchanged in MCF-7 cells undergoing G1- to S-transit; however, synthesis and steady state levels of cyclin D1 protein were increased by estradiol. Cdk4-associated Rb kinase activity was evident in MCF-7 cells by 6 h after estradiol exposure and was inhibited by antiestrogen. Cdk2 and Cdk4 protein levels were not altered by estrogen treatment; however, faster migrating, phosphorylated Cdk2 forms increased in estradiol-treated MCF-7 cells by 12 after release from growth arrest. Cdtk-inhibitory activities, associated with p27kip-1, were eliminated from growth-arrested MCF-7 cells after treatment with estradiol but were not eliminated from cells cotreated with estradiol and ICI 182,780. These findings suggest that estradiol regulates G1 progression in MCF-7 cells through direct effects upon Cdk activation, Rb phosphorylation, and by inducing elimination of Cdk inhibitors.
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It has been convincingly demonstrated that genotoxic stresses cause the accumulation of the tumor suppressor gene p53. One important consequence of increased p53 protein levels in response to DNA damage is the activation of a G1-phase cell cycle checkpoint. It has also been shown that G1-phase cell cycle checkpoints are activated in response to other stresses, such as lack of oxygen. Here we show that hypoxia and heat, agents that induce cellular stress primarily by inhibiting oxygen-dependent metabolism and denaturing proteins, respectively, also cause an increase in p53 protein levels. The p53 protein induced by heat is localized in the cytoplasm and forms a complex with the heat shock protein hsc70. The increase in nuclear p53 protein levels and DNA-binding activity and the induction of reporter gene constructs containing p53 binding sites following hypoxia occur in cells that are wild type for p53 but not in cells that possess mutant p53. However, unlike ionizing radiation, the accumulation of cells in G1 phase by hypoxia is not strictly dependent on wild-type p53 function. In addition, cells expressing the human papillomavirus E6 gene, which show increased degradation of p53 by ubiquitination and fail to accumulate p53 in response to DNA-damaging agents, do increase their p53 levels following heat and hypoxia. These results suggest that hypoxia is an example of a "nongenotoxic" stress which induces p53 activity by a different pathway than DNA-damaging agents.
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Few processed foods can be found that do not contain one or more of the thousands of different chemicals and materials that are food additives. According to recent estimates, about $5.5 billion worth of additives are used widely in the $385 billion U.S. food and beverage market. Throughout the 1990s, the U.S. market for food additives is expected to grow 4 to 6% annuallyto as much as $7 billion by 1995. The development and use of food additives is frequently driven by consumer demand and often becomes a balancing act between consumers' seemingly contradictory desires—the desire for more "natural" foods versus that for prepared, often microwaveable, convenience foods. The situation is complicated further by the desire for low-calorie, lowfat, and low-cholesterol foods. Health concerns and the desire for convenience foods will drive market growth for food additives, particularly for new products such as high-intensity sweeteners and fat replacers. The impact of these trends on ...
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The retinoblastoma gene product (the RB protein) is phosphorylated in a cell cycle-dependent manner and this modification is believed to be important for cells to progress through the cell cycle. We found that purified cdk2 (cyclin-dependent kinase/cell division kinase 2) can phosphorylate the RB protein in vitro at the sites phosphorylated in the cell. The timing of activation of cdk2 in the cell cycle was similar to that of the onset of phosphorylation of the RB protein. The kinase coprecipitated with the RB protein also exhibited a similar substrate specificity to cdk2 and a similar time course of activation during the cell cycle. We further showed that cdk2 formed a complex with the RB protein in vitro and that its formation was not competitively inhibited by the simian virus 40 large T antigen. These observations suggest that cdk2 or a cdk2-related protein is involved in the cell cycle-dependent phosphorylation of the RB protein.
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This article has no abstract; the first 100 words appear below. BREAST cancer is a major public health problem of great interest and importance to physicians in a variety of specialties. Since this topic was last reviewed in the Journal,¹ the incidence of the disease has increased dramatically, heightening concern among physicians and women in general. In addition, long-term results are now available from clinical trials initiated in the 1970s and 1980s to evaluate the usefulness of early detection with mammography and physical examination, breast-conserving treatment with limited breast surgery and irradiation, and adjuvant systemic therapy with hormonal therapy and chemotherapy. Furthermore, in the light of newly gained knowledge, new . . . Source Information From the Departments of Radiation Oncology, Beth Israel Hospital and the Dana–Farber Cancer Institute, and the Joint Center for Radiation Therapy, Harvard Medical School, Boston (J.R.H.); the Vincent T. Lombardi Cancer Research Center and the Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington, D.C. (M.E.L.); the Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy (U.V.); and the Departments of Epidemiology and Nutrition, Harvard School of Public Health and the Channing Laboratory, Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston (W.W.). Address reprint requests to Dr. Harris at the Harvard Joint Center for Radiation Therapy, 50 Binney St., Boston, MA 02115.
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Breast cancer is the second leading cause of death by cancer among women in the United States. The total cost of illness for breast cancer has been estimated to be $3.8 billion, of which $1.8 billion represents medical care costs. It has been estimated that breast cancer detected early is considerably less expensive than when the tumor is discovered at a later stage. Mass screening using mammography can improve early detection by as much as 15-35%. Cost-effectiveness studies have estimated that the costs of breast cancer screening range between $13,200 and $28,000 per year of life saved. The cost-effectiveness of breast cancer screening in the 40-49-year-old age group is controversial. Mass screening for breast cancer will probably increase total health care costs, but when all economic costs are included, screening appears to be more cost-effective than not screening.
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The growing proportion of processed foods in the average daily diet in industrialized countries is considered as a challenge to the food industry, not only to provide more variety to the food assortment, but also to cope with high nutritional quality standards. Industrial handling of food therefore includes the monitoring of numerous operations and conditions from the agricultural source, through processing, packaging and distribution. Various types of food raw materials are processed by different kinds of technological treatments, the main objectives being to guarantee wholesomeness, taste, nourishment and convenience. New processing methods combined with the cold chain distribution reduce micronutrient losses to a certain extent. We shall examine some of the critical technological operations with regard to losses of vitamins and minerals in representative examples of foods like milk, leafy vegetables, potatoes, etc. and compare the classical food preservation with more modern food handling. With the increasing demand of pre-prepared fresh, refrigerated or frozen foods, the contribution of the maintained micronutrients is of interest, especially with reference to modern eating habits, i.e. lowering the total food intake and improving the nutrient density in the normal diet plan.
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We have learned through the study of human breast cancer that this disease is the result of a combination of factors, among them external factors such as ionizing radiation, diet, socioeconomic status and endocrinologic, familial or genetic factors. Among all of these factors, the development of breast cancer is influenced by the reproductive history of the individual; lower risk of breast cancer has been reported in women that have had an early full-term pregnancy (109, 110, 154, 162).
Article
Synopsis We review information highlighting the multiple roles of both steroidal (primarily oestrogen) and polypeptide regulators of mammary epithelial cell growth, emphasising the work of our laboratory. Effects of both classes of hormones are complex and involve multiple interactions with non-tumour, host tissue. Oestrogen may induce growth regulatory polypeptide growth factors and interact with them in hormone dependent breast cancer. Progression of hormone-dependent breast cancer to hormone independence may involve multiple genetic mechanisms of oncogene activation, loss of the oestrogen receptor, or loss of hormone responsivity of other gene products. Initial carcinogenesis and progression of mammary epithelium to cancer probably also requires both proliferative stimuli (oestrogen, polypeptide growth factors) and genetic damage, leading to qualitatively different hormonal responses (hormone responsive cancer). Future therapies should be designed to block hormonal stimulation better and to interfere with necessary activated or induced components of malignant progression such as oncogenes or polypeptide growth factors receptor systems.
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This chapter discusses that the development of malignancy depends on interactions of inherited genetic factors, exposure to chemical carcinogens, damaging radiation, oncogenic viruses, mitogenic hormones, and other promotional agents. Studies of experimental animal model systems have allowed considerable insight into the mechanisms at work in the action of each of these components; however, the exact etiology of any human cancer is yet to be established. The chapter discusses the mechanisms of systemic estrogen actions in the breast cancer process. It explores mechanisms of loss of endocrine control in experimental and clinical breast cancer, commonly observed following systemic therapy. Loss of estrogenic control of breast cancer growth during malignant progression implies the existence of other growth control processes which take over in its place. Genetic events which evoke the malignant phenotype probably involve activation of dominant oncogenes and inactivation of dominant cancer suppressive genes. The mutation of cellular protooncogenes to yield highly active oncogenes is extremely important in chemical- and radiation-induced carcinogenesis.
Article
Erythrosine (diNa, tetraiodofluorescein) was nonmutagenic to the Ames/Salmonella typhimurium strains TA97a, TA98, TA100, TA102, and TA104, to a concentration of 2 mg/plate. No mutative intermediates were detected on metabolism by rat caecal cell-free extracts or rat liver S9 mixture; or on incubation with the comutagens, harman and norharman (+/- S9). Instead, an unexpected dose-dependent suppression in spontaneous reversion frequencies was observed (maximum approximately equal to 35% decrease). Erythrosine was antimutagenic to benzo[a]pyrene, but it did not decrease the mutagenicity of the other adduct-forming mutagen, 4-nitroquinoline N-oxide. The food dye was strongly antimutagenic to the bifunctional alkylating agent, mitomycin C, though it did not exhibit a similar effect on the mutagenicity of the corresponding monofunctional agent, methyl methanesulphonate. It partially depressed the mutagenic potentials of sodium azide. The antimutagenic effect of erythrosine on an intercalating agent, ethidium bromide, was discernible only at the highest dose (2 mg/plate). These results have been interpreted in terms of a genointeractive role of erythrosine. Erythrosine produced differential toxic effects in repair-deficient (TA97a, TA98, TA100) and repair-proficient (TA102, TA104) Salmonella tester strains; survival of the repair-deficient strains was found to be decreased. Photoinduced potentiation of erythrosine toxicity was observed, although light irradiation in the presence of erythrosine did not modify the reversion frequencies of the tester strains. The evidence strongly suggests that erythrosine, which exhibits nonmutagenicity in the Ames/Salmonella test, can interact with DNA repair enzymes and/or with DNA.
Article
The effects of erythrosine (Red 3), rose bengal B (Red 105) and thyroidectomy on the development of thyroid tumor were examined in male Wistar rats treated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Red 3 and Red 105 were used at 4% in the basal diet and were administered for 19 weeks from week 2 to 20. Thyroidectomy was performed by resection of the left lobe at week 4. Single injection of DHPN was performed intraperitoneally at 280 mg per 100 g body weight at the beginning of the experiment. Red 3 and Red 105 significantly promoted the development of thyroid tumors in thyroidectomized rats given DHPN, but had no significant effect in non-thyroidectomized rats. The incidence of thyroid tumors was 91% in rats with partial thyroidectomy, Red 3 and DHPN, 100% in rats with partial thyroidectomy, Red 105 and DHPN, and 64% in rats with partial thyroidectomy and DHPN. Serum TSH was 5.5 +/- 3.1 ng/ml in rats with partial thyroidectomy, Red 3 and DHPN, 2.1 +/- 2.2 ng/ml in rats with partial thyroidectomy, Red 105 and DHPN, and 1.5 +/- 0.5 ng/ml in rats with partial thyroidectomy and DHPN.
Article
Erythrosine increased the yield of sporulation minus mutants of Bacillus subtilis excision repair-proficient strain 168 by approximately equal to 400% at a concentration of 1 mg/ml under ambient light conditions. This mutagenic response was dose-dependent (0-1 mg/ml). Significantly, the food dye did not mutate the corresponding repair-deficient B. subtilis, hcr-9 (exc-). A decrease in the mutagenicity of erythrosine to B. subtilis strain 168 was apparent on metabolism by rat liver S9 mixture or by rat caecal cell-free extracts. Erythrosine did not exhibit differential toxicity to B. subtilis excision repair-proficient (168) and -deficient (hcr-9) strains, although it was highly toxic to both strains. This indicated non-involvement of excision repair in the dye-mediated toxic reactions.
Article
Although much attention has been paid to the removal of hormones from sera and to the development of serum-free media for studies on hormone-responsive cells in culture, little consideration has been given to the possibility that the media components themselves may have hormonal activity. We have found that phenol red, which bears a structural resemblance to some nonsteroidal estrogens and which is used ubiquitously as a pH indicator in tissue culture media, has significant estrogenic activity at the concentrations (15-45 microM) at which it is found in tissue culture media. Phenol red binds to the estrogen receptor of MCF-7 human breast cancer cells with an affinity 0.001% that of estradiol (Kd = 2 X 10(-5) M). It stimulates the proliferation of estrogen receptor-positive MCF-7 breast cancer cells in a dose-dependent manner but has no effect on the growth of estrogen receptor-negative MDA-MB-231 breast cancer cells. At the concentrations present in tissue culture media, phenol red causes partial estrogenic stimulation, increasing cell number to 200% and progesterone receptor content to 300% of that found for cells grown in phenol red-free media, thereby reducing the degree to which exogenous estrogen is able to stimulate responses. The antiestrogens tamoxifen and hydroxytamoxifen inhibit cell proliferation below the control level only when cells are grown in the presence of phenol red; in the absence of phenol red, the antiestrogens do not suppress growth. The estrogenic activity of phenol red should be considered in any studies that utilize estrogen-responsive cells in culture.
Article
MT2 cells, a clonal cell line of MTW9/PL cells originally obtained from a mammary adenocarcinoma, from estrogen-responsive tumors in Wistar-Furth rats. o,p'-DDT supports MT2 tumor growth at a rate similar to 17 beta-estradiol. This effect of o,p'-DDT is dose-dependent and specific, since the DDT congener p,p'-DDD, which does not bind to tumor estrogen receptors, does not support tumor growth. This is the first demonstration that DDT can support the growth of an estrogen-responsive tumor.
Article
Serine 118 is definitively identified as a major site of phosphorylation in the human estrogen receptor expressed in COS-1 cells treated with estradiol or phorbol ester. At least 30% of the estrogen receptor appears to be phosphorylated on serine 118 after treatment with estradiol or phorbol ester. Human estrogen receptor was expressed in COS-1 cells and labeled in vivo with [32P]orthophosphate in the presence of estradiol or phorbol ester. Immunopurified receptor was digested with cyanogen bromide. The most heavily labeled peptide (7 kilodaltons) was identified as amino acids 110-174 by microsequencing. Manual Edman degradation released a major portion of the 32P-label in the peptide at serine 118. A mutant with serine 118 replaced by alanine (S118A) had 80% less 32P-label in the 7 kilodalton peptide. Estrogen receptor labeled in vivo with [32P]-orthophosphate in the presence of estradiol or phorbol ester migrates electrophoretically as a doublet. The major difference between the bands is phosphorylation of serine 118 in the upshifted band. The mutant S118A does not show an upshifted band. Labeling of the estrogen receptor with [35S]methionine indicates that > or = 30% of the receptor is upshifted and suggests that > or = 30% of the receptor is phosphorylated on serine 118.
Article
The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.
Article
Chemotherapeutic and DNA-damaging agents were found to increase p53 site-specific DNA binding in human breast and rat liver epithelial WBrasII cells which produce mutant p53. Increased p53 site-specific DNA binding by chemotherapeutic or DNA-damaging agents was also induced in transfected Saos-2 cells producing wild type or transforming mutant p53. Therefore, exposure of cells containing a transforming p53 mutant to chemotherapeutic or DNA-damaging agents may potentially enhance their transformation state and tumorigenic potential.
Article
Upon cellular DNA damage, the p53 tumor suppressor protein transmits a signal to genes that control the cell cycle and apoptosis. One function of p53 that is important for its role in this pathway is its ability to function as a sequence-specific transcriptional activator. We demonstrate here that short single DNA strands can markedly stimulate the ability of human and murine p53 proteins to bind specifically to a p53 response element in supercoiled DNA. We also show that single-stranded DNA does not stimulate binding by a truncated p53 that lacks the C-terminal domain. Finally, we establish that a peptide spanning the p53 C-terminus has the ability in trans to stimulate sequence-specific DNA binding by p53 dramatically. These data taken together suggest a model in which the p53 C-terminus can recognize DNA structures resulting from damage-induced lesions, and this interaction can be propagated to regulate positively p53 sequence-specific DNA binding.
Article
Insertion/deletion (IDL) mismatches in DNA are lesions consisting of extra bases on one strand. Here, the binding of p53 and its 14 kDa C-terminal domain to DNAs containing one or three 3-cytosine IDL mismatches was examined. Electron microscopy showed that both p53 forms bound predominantly as tetramers at the lesions while single-stranded binding proteins did not bind. Gel retardation assays showed that p53 formed highly stable complexes when the DNA contained the IDL mismatches, but only unstable complexes when the DNA lacked lesions (but did contain free ends). The highly stable complexes had a half-life of > 2 hr, suggesting that upon encountering lesions, p53 may recruit other proteins to the site, providing a signal for DNA damage.
Article
Charles J. Sherr Howard Hughes Medical Institute Department of Tumor Cell Biology St. Jude Children’s Research Hospital 332 North Lauderdale Memphis, Tennessee 38104 Recent advances in our understanding of the cell division cycle are now tying the functions of Gl phase regulators to diverse processes involving signal transduction, differ- entiation, senescence, apoptosis, and malignant transfor- mation. What determines the rate of Gl phase progression, and how do cells integrate mitogenic and antiproliferative signals with the cell cycle machinery? Lessons From Budding Yeast In Saccharomyces cerevisiae, a single 34 kDa cyclin- dependent kinase (cdk) (p34cDCZB/cdc2, also known as cdkl) serves as a master controller of the cell cycle, assembling sequentially into active holoenzyme complexes with Gl, S phase, or mitotic cyclins temporally to direct distinct transitions (reviewed by Nasmyth, 1993; Reed, 1992). In the presence of appropriate nutrients, Gl cells that reach a critical size initiate DNA replication, form buds, and dupli- cate their spindle bodies in preparation for subsequent division. Gl cyclins (Clnl, Cln2, and Cln3) are required for these processes (Richardson et al., 1989) (see Figure I), and their overexpression contracts Gl phase and de- creases cell size. Cln3-Cdc28 is present throughout Gl, and its kinase activity appears necessary for the subse- quent transcriptional activation of the CLN7 and CLN2 genes (Tyers et al., 1993). In turn, the induced Clnl and Cln2 proteins associate with Cdc28, whose kinase activity further stimulates CLN7 and CLN2 transcription. CLN7 and CLN2 gene expression is controlled by a heterodimeric transcription factor composed of Swi4 and Swi6, and Cln- CdcPm Schwab and Nasmyth, 1993). The kinase activities of Clb-Cdc28 complexes are held in check by an inhibitory protein (p40sfc’) (Mendenhall, 1993) that accumulates early in Gl and is degraded shortly before S phase (Schwab et al., 1994). Phosphorylation of ~40~‘~’ by Clnl,Cln2-Cdc28 might trigger its ubiquitin- mediated degradation, thereby enabling the Cln-regulated kinases to control S phase entry indirectly. Haploid Gl phase cells can also undergo cell cycle ar- rest and mate to form diploids. Conjugation is provoked by pheromones (a and a factors), secreted by cells of oppo- site mating types, that trigger a receptor-mediated sig- naling pathway (serpentine receptor-heterotrimeric G
Article
Five small case-control studies have examined the relationship between exposure to organochlorines and the risk of breast cancer and have found inconsistent results. In these studies, organochlorine levels in breast cancer patients were measured after (or at most 6 months before) diagnosis. We tested the hypothesis that organochlorines are a risk factor for breast cancer, using prospectively gathered data on serum levels of DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] (the main metabolite of the pesticide DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane]) and polychlorinated biphenyls (PCBs). Study subjects belonged to a cohort of 57,040 women (46,629 white, 8123 black, and 2288 Asian) from the San Francisco Bay Area who took a multiphasic health examination, independent of concern about risk of breast cancer, in the late 1960s. At that time, a sample of blood was obtained, then frozen and stored. Follow-up was through December 31, 1990. We conducted a nested case-control study of 150 case patients and 150 matched control subjects. A random sample of 50 women per racial/ethnic group who had been diagnosed with breast cancer more than 6 months after the multiphasic examination (mean follow-up = 14.2 years) was selected, and each case patient was matched to a cancer-free control subject. Matched analyses found no differences in the case patients' and control subjects' serum levels of DDE (mean difference = 0.2 parts per billion [ppb]; 95% confidence interval [CI] = -6.7, 7.2) or PCBs (mean difference = -0.4 ppb; 95% CI = -0.8, 0.1). DDE levels, however, tended to be higher among black case patients compared with black controls (mean difference = 5.7 ppb; 95% CI = -3.3, 14.8), and PCBs were lower among white case patients compared with white controls (mean difference = -0.6 ppb; 95% CI = -1.2, -0.1). Organochlorine levels were significantly higher among black and Asian women compared with white women. The mean difference for DDE was 11.0 ppb for black women (95% CI = 4.3, 17.6) and 12.6 ppb for Asian women (95% CI = 6.0, 19.2); for PCBs, the respective differences were 0.8 ppb for black women (95% CI = 0.2, 1.4) and 1.4 ppb for Asian women (95% CI = 0.8, 1.9). The results were not altered by adjusting for relevant confounders, and the lack of association between exposure to organochlorines and breast cancer was present regardless of length of follow-up, year of diagnosis, or the case patient's menopausal and estrogen-receptor status. The data do not support the hypothesis that exposure to DDE and PCBs increases risk of breast cancer. Future investigations must consider the biologic mechanisms involved and variations in exposure to chemical pollutants and of breast cancer incidence rates among diverse groups of women.
Article
Many recent studies have implicated dietary factors in the cause and prevention of important diseases, including cancer, coronary heart disease, birth defects, and cataracts. There is strong evidence that vegetables and fruits protect against these diseases; however, the active constituents are incompletely identified. Whether fat per se is a major cause of disease is a question still under debate, although saturated and partially hydrogenated fats probably increase the risk of coronary heart disease. One clear conclusion from existing epidemiologic evidence is that many individuals in the United States have suboptimal diets and that the potential for disease prevention by improved nutrition is substantial.
Article
Damage to cellular DNA greatly increases the levels of the tumor-suppressor gene p53 and induces cell cycle arrest in G1. A critical function of wild-type p53 is its ability to bind to specific DNA sequences. The effect of DNA damage on the sequence-specific DNA-binding properties of cellular p53 was investigated using DNA gel mobility-shift assays with nuclear extracts from NIH-3T3 cells. DNA damage (initiated by radiation) induced a rapid, cycloheximide-sensitive increase in the levels of nuclear p53-DNA binding activity and an increase in the half-life of the p53 protein. Increased p53-DNA binding activity could be detected at low (0.2 Gy), non-lethal doses of radiation. The tumor promoter 12-O-tetradecanoyl phorbol 13-acetate (TPA) attenuated the DNA damage-induced increase in p53-DNA binding activity by decreasing the half-life of the p53 protein. The tumor promoter properties of TPA may therefore be mediated by interfering with the cellular p53 response to DNA damage. The increased levels of p53 bound to specific DNA sequences following DNA damage may induce cell cycle arrest. p53-mediated growth arrest could occur by inhibition of DNA replication and/or alterations in transcription of cell cycle genes.
Article
Certain chemicals in the environment are estrogenic. The low potencies of these compounds, when studied singly, suggest that they may have little effect on biological systems. The estrogenic potencies of combinations of such chemicals were screened in a simple yeast estrogen system (YES) containing human estrogen receptor (hER). Combinations of two weak environmental estrogens, such as dieldrin, endosulfan, or toxaphene, were 1000 times as potent in hER-mediated transactivation as any chemical alone. Hydroxylated polychlorinated biphenyls shown previously to synergistically alter sexual development in turtles also synergized in the YES. The synergistic interaction of chemical mixtures with the estrogen receptor may have profound environmental implications. These results may represent a previously uncharacterized level of regulation of estrogen-associated responses.
Article
Estrogens play a critical role in the etiology of found breast cancer. Estradiol promotes the growth of breast cancer cells in vivo and in vitro. Exogenous estrogens in both the environment and in the human diet increase the growth of breast cancer cells in vitro. A role for xenoestrogens in breast cancer etiology has been proposed but remains controversial. We examined the effects of the xenoestrogenic pesticide 1,1,1-trichloro-2,2-bis(chlorophenyl)ethane (DDT) on estrogen-receptor (ER)-positive MCF-7 and T-47D human breast cancer cells as well as on ER-negative HS 578Bst breast cancer cells and rat liver cells. Estradiol and DDT were found to increase the growth of MCF-7 cells in the presence of insulin. The activity of cyclin-dependent kinase (Cdk)2 increased in growth-arrested T-47D and MCF-7 cells treated with beta-estradiol or DDT. The steroidal antiestrogen ICI 182,780 prevented both growth and Cdk2 activation induced by estradiol or DDT. Increased phosphorylation of Cdk2 and the retinoblastoma protein (pRb1O5) was observed in ER-positive cells treated with DDT or estradiol. Cdk2 activity was not affected by DDT or estradiol in ER-negative HS 578Bst breast cancer cells or in rat liver epithelial cells. Cyclin D1 protein synthesis was increased by DDT and estradiol in MCF-7 cells. DDT and estradiol-induced ER-dependent transcriptional activation of estrogen response elements (EREs) in stably transfected MVLN cells, and ERE activation by low doses of DDT was increased by insulin. These findings suggest that DDT can stimulate breast cancer cells to enter into the cell cycle by directly affecting key regulatory elements. The relative potency of DDT in inducing cell-cycle progression appears to be only 100-300 times less than that of estradiol when measured in the presence of insulin. Therefore, the cancer risks associated with DDT exposure may be greater than first thought, especially when additional mitogenic stimuli are present.
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