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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential danger to humans of exposure to chemicals shown to be carcinogenic in animals has become increasingly clear in the last 20 years. A gap still exists, however, between the appreciation of the risk by scientists and the willingness of public health authorities to reduce it. Three pesticides, shown repeatedly to produce over a dozen different types of cancer in rats and mice, were discovered in inordinately high concentrations in Israeli milk and dairy products. The three pesticides--alpha-BHC, gamma-BHC (lindane), and DDT--had been shown to be present for ten years or more at mean concentrations up to 100 times those found in U.S. dairy products--with resultant concentrations in breast milk being possibly 800 times greater than those in the United States--yet neither the Ministry of Health nor the Israel Cancer Association made any apparent moves either to warn the public or to rectify the situation. A small consumer organization, Consumer Shield, brought the issue into the open. Through public pressure, court action, and the threat of further legal redress--and despite repeated attacks in the media by the milk producers, the Ministry, and the Cancer Association--Consumer Shield forced the authorities to outlaw the use of alpha-BHC and lindane (DDT no longer being in general use). The ban resulted in a precipitous drop in the concentrations of these substances in Israeli milk. Recent epidemiological and laboratory findings suggest that the dramatic drop in breast cancer mortality rates subsequent to the pesticide ban could be a direct result of that ban.
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PMID:Carcinogens in Israeli milk: a study in regulatory failure. 837 52

The estrogenic action of some persistent organochlorine pesticide residues may play a role in the progression of hormonally responsive tumors of the breast and uterus. The prototypical xenoestrogen o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT) acts by binding and activating the estrogen receptor (ER). The present study focuses attention on the mechanisms through which another organochlorine compound, beta-hexachlorocyclohexane (beta-HCH), exerts estrogen-like effects in human breast cancer cells. Both o,p'DDT and beta-HCH stimulated proliferation in a dose-dependent manner in the ER-positive cell lines MCF-7 and T47D but not in the ER-negative lines MDA-MB231, MDA-MB468, and HS578T. Both compounds produced an increase in the steady state level of pS2 mRNA in MCF-7 cells. These responses were equal in magnitude to the maximal effect of estradiol, and they were inhibited by inclusion of the antiestrogen ICI164384. On the other hand, when tested in a competitive binding assay, beta-HCH did not displace 17beta-[3H]estradiol from the ER even at a concentration that was 40,000-fold higher than the tracer steroid. Furthermore, nuclear retention of the ER during homogenization procedures was induced by a 2- or 24-h treatment of MCF-7 cells with o,p'-DDT and 17beta-estradiol but not by treatment with beta-HCH; this indicates that beta-HCH nether activates the ER, nor is it converted intracellularly to an ER ligand. Transcriptional activation by beta-HCH occurs in estrogen-responsive GH3 rat pituitary tumor cells transfected with a luciferase reporter construct driven by a complex 2500-bp portion of the PRL gene promoter; this trans-activation response is inhibited by inclusion of ICI164384. However, beta-HCH is ineffective in stimulating a reporter construct driven only by a consensus estrogen response element and a minimal promoter derived from the herpes simplex virus thymidine kinase gene. Thus, beta-HCH cannot act on a simple, single estrogen response element; rather, it requires the combinatorial regulation found in a complex promoter. These data are consistent with the notion that beta-HCH stimulation of cell proliferation and gene expression is ER dependent, but its action is not through the classic pathway of binding and activating the ER. beta-HCH may represent a new class of xenobiotic that produces estrogen-like effects through nonclassic mechanisms and, therefore, may be of concern with regard to breast and uterine cancer risk.
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PMID:Novel estrogenic action of the pesticide residue beta-hexachlorocyclohexane in human breast cancer cells. 896 93

The pesticide residues 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2,2-trichloroethane (o,p'-DDT) and beta-hexachlorocyclohexane (beta-HCH) act as weak estrogens, producing uterotrophic responses in ovariectomized rodents and stimulating human breast cancer cells in culture. Such activity suggests that these compounds may act as tumor promoters in estrogen-responsive tissues. Organochlorine compounds such as o,p'-DDT and beta-HCH are concentrated in body fat. The present report tests whether sufficient compound can be released from fat depots to produce estrogenic effects in uteri of ovariectomized mice. Adult animals were "loaded" with test compound by three daily injections of vehicle (DMSO), 17beta-estradiol (E2), beta-HCH, or o,p'-DDT. Uterotrophic effects were assessed at 24 h after the last loading dose of test compound and at 2 weeks after the loading regimen, with or without a prior 2-day period of fasting. The initial 3-day treatment with either beta-HCH or o,p'-DDT doubled the relative dry weight of the uterus: 102 +/- 8.6 mg/kg body weight (BW) and 104 +/- 4.4 mg/kg BW for beta-HCH and o,p'-DDT, respectively, compared to 49 +/- 1.9 mg/kg BW for vehicle-treated animals. E2-treated animals had uterine dry weights of 228 +/- 11 mg/kg BW. After 2 weeks without further treatment, a 2-day fast produced a decrease in body mass of 4.1 g/animal (fasted, 25.9 +/- 1.89 g versus fed, 30.0 +/- 2.82 g). Animals that had been loaded with beta-HCH and fasted had uterine weights (88 +/- 12 mg/kg BW) significantly greater (P < 0.05) than those of vehicle-loaded, fasted animals (51 +/- 2.9 mg/kg BW) or of beta-HCH-loaded, fed animals (59 +/- 4.6 mg/kg BW). The uterine weights of the fasted and fed o,p'-DDT-loaded or E2-loaded animals were not different from those of control weights. The difference between wet and dry weights showed that fasting of beta-HCH-loaded animals also increased water imbibition in the uterus; there was no effect from fasting in the other groups. Generally, epithelial cell height reflected the same responses as uterine weight with the exception that cell heights of beta-HCH-loaded, fed animals were slightly higher (P < 0.05) than corresponding controls, indicating that there may have been some active compound available to the tissues even without fasting. The effects of fasting show that during periods of lipolysis beta-HCH can be released in quantities sufficient to stimulate estrogen target tissues, suggesting a novel mechanism linking obesity and the progression of estrogen-responsive tumors. The lack of effect from fasting in o,p'-DDT-loaded animals indicates that these compounds are differentially mobilized from fat depots.
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PMID:Xenobiotics released from fat during fasting produce estrogenic effects in ovariectomized mice. 904 Nov 87

It has been suggested that there is a positive correlation between increased incidence of breast cancer and the presence of organochlorine residues such as DDT and HCH in breast tissues in the United States. To study possible biochemical links between these two parameters, we have examined the effect of o,p'-DDT, the most estrogenic congener of the DDT family of chemicals and beta-HCH on protein phosphorylation activities in MCF-7, a line derived from human breast cancer cells. Both of these organochlorine chemicals were found to be potent activators of protein kinases. Among kinases activated, protein tyrosine kinases (PTK) appear to be most affected as judged by the antagonistic action of genistein, a class-specific PTK inhibitor. Moreover, these organochlorines were found to activate PTK even under cell-free conditions, indicating that they are likely to interact directly with the target protein tyrosine kinase. As a result of immunoprecipitation with specific antibodies, and testing on the action of these organochlorines, we could show that the major kinase activated by o,p'-DDT is c-Neu (= c-erbB2 product protein). The concentrations of these organochlorines required to activate c-Neu were extremely low (0.1-1 nM range), whereas an inactive analog p,p'-DDT showed no stimulatory property even at 100 nM. Such an action of these organochlorine compounds were not antagonized by the presence of 1 microM tamoxifen, indicating that it is not mediated through the estrogen receptor. In addition, their c-Neu activating actions were specifically antagonized by a c-Neu antibody known to interact with the extracellular domain of c-Neu only without affecting the EGF receptor. Moreover, these chemicals did not cause downregulation of the EGF receptor during the 72 hour test period. Together these data indicate that the action of these chemicals on c-Neu kinase is very specific.
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PMID:Activation of c-Neu tyrosine kinase by o,p'-DDT and beta-HCH in cell-free and intact cell preparations from MCF-7 human breast cancer cells. 944 65

Several studies have shown that some organochlorine compounds act like estrogen in certain animals and in vitro cell culture systems, and therefore, there is a possibility that they could promote the process of tumorigenesis in breast cancer cells. In our previous study, two representative organochlorines, 1,1,1-trichloro 2-o-chlorophenyl-2'-p-chlorophenyl ethane (o,p'-DDT) and beta-1,2,3,4,5,6-hexachlorocyclohexane (beta HCH), were found to directly activate the protein tyrosine kinase of Neu (c-erbB-2 proto-oncogene product) immunoprecipitates isolated from MCF-7 breast cancer cells. In the current study, we also found that 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) at 1 nM and alpha-HCH isomers at 100 nM could also significantly activate protein tyrosine kinase of Neu immunoprecipitates in a cell-free system. We also found that organochlorines result in an increase of Neu protein tyrosine kinase after intact cell treatment in estrogen-depleted medium. This Neu kinase activation by beta-HCH (100 nM) was blocked when the cells were pretreated with Neu mRNA antisense oligonucleotide (p < 0.07, Student's t-test). Endogenously added alpha-, beta-, and gamma-HCH, o,p'-DDT, 2,2'-dichlorobiphenyl (2,2'-PCB), and 2,4,5-T at 100 nM were found to promote foci formation in postconfluent cultures of this cell line. This stimulatory effect caused by 17beta-estradiol, o,p'-DDT, and beta-HCH on foci formation was inhibited by coincubation with Neu monoclonal antibody (p < 0.05). Those two events induced by organochlorines (i.e., Neu kinase activation and foci formation) seemed causally correlated.
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PMID:Correlation between the activation of Neu tyrosine kinase and promotion of foci formation induced by selected organochlorine compounds in the MCF-7 model system. 1048 16

Information on the association between exposure to beta-hexachlorocyclohexane (beta-HCH), hexachlorobenzene (HCB) or polychlorinated biphenyls (PCBs) and the incidence of breast cancer is inconclusive. However, exposure to such compounds is a public health concern in Mexico and is subject to recent regulation. Serum levels of beta-HCH, HCB and PCBs were analysed in 95 histologically confirmed breast cancer cases and 95 hospital controls, 20-79 years of age, from Mexico City, enrolled between March 1994 and April 1996. After adjusting for established risk factors, there was no evidence of a relationship between beta-HCH, HCB and PCBs and breast cancer risk (OR for beta-HCH tertile 3 versus tertile 1: 1.05 95% CI 0.46-2.40; OR for HCB tertile 3 versus tertile 1: 0.46 95% CI 0.20-1.07; OR for PCBs 1.31 95% CI 0.33-5.21 for the high category of exposure). This study lends no support to the case for a role for beta-HCH, HCB or PCBs in breast cancer aetiology.
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PMID:Serum levels of beta-hexachlorocyclohexane, hexachlorobenzene and polychlorinated biphenyls and breast cancer in Mexican women. 1198 30

The levels of some organochlorine pesticides (OCP)s (hexachlorobenzene, HCB, alpha-hexachlorocyclohexane, alpha-HCH, beta-HCH, gamma-HCH, heptachlorepoxide, HE, bis (4-chlorophenyl)-1,1-dichloroethene, p.p'DDE, bis (4-chlorophenyl)-1,1,1-trichloroethane, p.p' DDT and total DDT (E-DDT) and antioxidant enzyme activities namely Cu, Zn superoxide dismutase (SOD), catalase (CAT), selenium-dependent glutathione peroxidase (Se-GSH-Px), total glutathione peroxidase (T-GSH-Px), selenium independent glutathione peroxidase (GSH-Px II), glutathione reductase (GRd), level of reduced glutathione (GSH) and lipid peroxidation (LP), glutathione S-transferase (GST) activity toward several substrates including 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (ENPP) were measured in tumor and surrounding tumor free tissues of 24 female breast cancer patients and was evaluated whether there exist any association between the levels of OCPs and antioxidants. The mean levels of GSH, alpha-BHC, gamma-BHC and HE, and activities of SOD, Se-GSH-Px, T-GSH-Px, GSH-Px II,GRd, GST CDNB, and GST DCNB were significantly higher in tumors than in controls. In tumors, significant correlations were noted between: SOD and y-BHC; Se-GSH-Px and gamma-BHC; T-GSH-Px and gamma-BHC; GSH-Px II and alpha-BHC, gamma-BHC; GSH and alpha-BHC, gamma-BHC, HE; GRd and alpha-BHC; CDNB GST and alpha-BHC, gamma-BHC. These results show that free-radical mediated oxidative stress is, at least partly, associated with some of these OCP residues in human breast tumors.
Breast Cancer Res Treat 2002 Mar
PMID:The organochlorine pesticide residues and antioxidant enzyme activities in human breast tumors: is there any association? 1203 8

Environmental contamination by pesticides has been documented in biotic and abiotic components. These persistent organic pollutants are lipid soluble, nonbiodegradable, and endocrine disrupters. The present study was therefore planned to determine whether the levels of these pesticides like DDT and its metabolites DDD and DDE, dieldrin, heptachlor, and HCH and its isomers (alpha, beta, and gamma) were higher in blood of breast cancer patients when compared with normal women who did not suffer from major diseases like blood pressure, tuberculosis, diabetes, thyroid dysfunction, arthritis, cancer, etc. and had not undergone any major surgery. The results indicated that organochlorine pesticides taken for analysis were found significantly high in breast cancer patients irrespective of age, diet, and geographic distribution.
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PMID:Breast cancer incidence and exposure to pesticides among women originating from Jaipur. 1243 82

We conducted a study in Egypt to assess the determinants of organochlorine serum levels among premenopausal women and the risk of premenopausal breast cancer for women with high organochlorine serum levels. We included 69 breast cancer patients and 53 controls consisting of visitors to the hospitals of the cancer patients. We found low levels of dichlorodiphenyldichloroethylene (DDE), total dichlorodiphenyltrichloroethane, and beta-hexacholorhexane (beta-HCH) in most subjects. Mean DDE levels were 12.7 +/- 20.3 ppb for cases and 16.6 +/- 30.1 ppb for controls (P = 0.60); beta-HCH levels were 2.1 +/- 3.8 ppb for patients and 2.1 +/- 3.9 ppb for controls (P = 0.71). Interestingly, subjects with low levels had breast fed their children for an average period of 18 months. Women with no lactation history had much higher organochlorine levels than women who breast fed (P = 0.002 for DDE). Younger age, older age at first childbirth, and shorter duration of breast feeding were significant predictors of higher levels of serum DDE levels. Younger age, older age at first childbirth, and higher body mass index were significant predictors of higher beta-HCH levels. This study suggests that organochlorine serum levels in Egyptian women are quite low, but indicates an effect of breast feeding in eliminating organochlorines, which would imply exposure to children. Organochlorine serum level was not a risk factor of breast cancer in this population.
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PMID:Serum organochlorine levels and history of lactation in Egypt. 1285 90

Due to its lipophilicity and persistence, an organochlorine compound, beta-hexachlorocyclohexane (beta-HCH), is known to frequently accumulate in human adipose and breast tissues. An epidemiological study has indicated that exposure to beta-HCH could be one of the significant environmental risk factors for the development of human breast cancers. Additionally, beta-HCH has recently been identified as an environmental estrogen capable of activating estrogen receptor (ER) through a ligand-independent pathway. In the present investigation, we examined the impact of long-term in vitro exposure to beta-HCH on cell transformation and the metastatic potentials of MCF-7 cells. We found that continuous exposure of MCF-7 cells to beta-HCH at 100 nM and 1 microM or to 17beta-estradiol (E(2)) at 1 nM for up to 13 months (33 passages) not only enhanced their transformation tendencies but also promoted their invasiveness. Western blot analysis revealed that beta-HCH induced transformation-related biochemical changes in MCF-7 cells, such as a decline in the levels of ERalpha and p44/42 MAP kinase and a significant increase in expression of c-ErbB2 and MMP-9 levels. In contrast, long-term E(2) treatment resulted in the downregulation of ERalpha and p44/42 MAP kinase and upregulation of MMP-9 only, but no changes in c-ErbB2. Together, these results indicate that these biochemical changes induced by beta-HCH are consistent with the events taking place in these cells to promote the phenotypical expression of transformed cells. Our results provide the in vitro mechanistic basis supporting the hypothesis that beta-HCH is one of the epigenetic risk factors assisting the progression of breast cancer cells to an advanced state of malignancy.
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PMID:Long-term exposure to beta-hexachlorocyclohexane (beta-HCH) promotes transformation and invasiveness of MCF-7 human breast cancer cells. 1294 64


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