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

This review is an attempt to comprehend the diverse groups of environmental chemical contaminants with a potential for pathogenesis of breast cancer, their probable sources and the possible mechanisms by which these environmental contaminants act and interplay with other risk factors. Estrogens are closely related to the pathogenesis of breast cancer. Oxidative catabolism of estrogen, mediated by various cytochrome P450 enzymes, generates reactive free radicals that can cause oxidative damage. The same enzymes of estrogenic metabolic pathways catalyze biological activation of several environmental (xenobiotic) chemicals. Xenobiotic chemicals may exert their pathological effects through generation of reactive free radicals. Breast tissue can be a target of several xenobiotic agents. DNA-reactive metabolites of different xenobiotic compounds have been detected in breast tissue. Many phase I and II xenobiotic metabolizing enzymes are expressed in both normal and cancerous breast tissues. These enzymes play a significant role in the activation/detoxification of xenobiotic and endogenous compounds including estrogens. More than 30 carcinogenic chemicals are present in tobacco smoke; many of them are fat-soluble, resistant to metabolism and can be stored in breast adipose tissue. Similarly, pesticides are also known to cause oxidative stress; while some act as endocrine disruptor, some are shown to suppress apoptosis in estrogen sensitive cell lines. Reports have shown an association of smoking (both active and passive) and pesticides with breast cancer risk. However, the issues have remained controversial. Different mutagenic substances that are generated in the cooking process e.g., heterocyclic amines and polycyclic aromatic hydrocarbons (PAHs) can be a threat to breast tissue. PAHs and dioxins exert their adverse effects through the aryl hydrocarbon receptor (AhR), which activates several genes involved in the metabolisms of xenobiotic compounds and endogenous estrogens. These chemicals also induce AhR-dependent mitochondrial dysfunction. Many of the environmental pollutants suppress the immune system, which are implicated to risk. A better understanding about the biological effects of different environmental carcinogenic compounds and determination of their impact on rising incidence of breast cancer will be beneficial in improving preventive policy against breast cancer.
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PMID:Environmental contaminants in pathogenesis of breast cancer. 1692 30

The aryl hydrocarbon receptor (AhR) is an evolutionarily conserved transcription factor bound and activated by ubiquitous environmental pollutants. Historically, the AhR has been studied for its transcriptional regulation of genes encoding cytochrome P450 enzymes, which metabolize many of these chemicals into mutagenic and toxic intermediates. However, recent studies demonstrate that the AhR plays an important role in the biology of several cell types in the absence of environmental chemicals. Here, this paradigm shift is discussed in the context of a putative role for the AhR in mammary gland tumorigenesis. Data demonstrating high levels of constitutively active AhR in mammary tumors are summarized. Particular focus is placed on the likelihood that the AhR contributes to ongoing mammary tumor cell growth and on the possibility that the AhR inhibits apoptosis while promoting transition to an invasive, metastatic phenotype. A working model is proposed that may help explain the sometimes contradictory outcomes observed after AhR manipulation and that serves as a blueprint for the design of therapeutics which target the AhR in breast cancer. The theme that malignant cells reveal the functions for which the AhR has been evolutionarily conserved is presented throughout this discussion.
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PMID:A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. 1697 84

Aminoflavone (AF) is entering clinical trials. We recently reported that AF induces DNA-protein cross-links (DPC) and gamma-H2AX in MCF-7 human breast cancer cells. To elucidate the mechanism of action of AF and provide biomarkers indicative of AF activity, we correlated AF activity profile (GI(50)) with gene expression patterns in the NCI-60 cell lines. Sulfotransferases (SULT) showed the highest positive correlation coefficients among approximately 14,000 probe sets analyzed (r = 0.537, P < 0.001). Stable transfection of SULT1A1 into AF-resistant MDA-MB-231 cells sensitized these cells to AF. AF produced DPCs, gamma-H2AX foci, and S-phase arrest in the SULT1A1-transfected but not in the parent MDA-MB-231 cells. Conversely, cells in which SULT1A1 was knocked down by small interfering RNA failed to induce gamma-H2AX. Inhibition of SULTs and cytochrome P450 (CYP) enzymes by natural flavonoids blocked the antiproliferative activity of AF and the formation of AF-DNA adducts. AF also induces SULT1A1 and CYP expression in MCF-7 cells, suggesting the existence of an aryl hydrocarbon receptor-mediated positive feedback for AF activation by CYP and SULT1A1. Metabolism studies showed that AF can be oxidized by CYP at two amino groups to form N-hydroxyl metabolites that are substrates for bioactivation by SULTs. We propose that both N-sulfoxy-groups can be further converted to nitrenium ions that form adducts with DNA and proteins. The results reported here show the importance of SULT1A1 and CYP for AF activation and anticancer activity. They also suggest using SULT1A1 and gamma-H2AX as biomarkers for prediction of AF activity during patient selection and monitoring of clinical trials.
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PMID:Activation of aminoflavone (NSC 686288) by a sulfotransferase is required for the antiproliferative effect of the drug and for induction of histone gamma-H2AX. 1701 23

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which requires heterodimerization with the Ah receptor nuclear translocator (Arnt) for function. Arnt is also a dimerization partner of the hypoxia inducible factor 1alpha (HIF-1alpha) for the hypoxia signaling. Additionally, Arnt is found to be a potent coactivator of the estrogen receptor (ER) signaling. Thus we examined whether the presence of an increased amount of AhR may suppress both the HIF-1alpha and ER signaling pathways by sequestering Arnt. We tested our hypothesis using a human AhR construct C Delta553 which is capable of heterodimerizing with Arnt in the absence of a ligand. Transient transfection studies using a corresponding luciferase reporter plasmid in MCF-7 cells showed that C Delta553 effectively suppressed the AhR, HIF-1alpha, and ER signaling pathways. Reverse transcription/real-time QPCR data showed that C Delta553 blocked the up-regulation of the target genes controlled by AhR (CYP1A1), HIF-1alpha (VEGF, aldolase C, and LDH-A), and ER (GREB1, pS2, and c-myc) in MCF-7 cells. Since both HIF-1alpha and ER are highly active in the ER-positive breast cancer, C Delta553 has the potential to be developed as a protein drug to treat breast cancer by blocking these two signaling pathways.
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PMID:A truncated Ah receptor blocks the hypoxia and estrogen receptor signaling pathways: a viable approach for breast cancer treatment. 1714 Feb 57

In the present study we examined the ability of 3,3',4,4',5-pentachlorinated biphenyl [PCB126 (polychlorinated biphenyl 126)], a prototypical AHR (aryl hydrocarbon receptor) agonist, and 2,2',4,6,6'-PCB (PCB104), which does not activate AHR, to induce the recruitment of ERalpha (oestrogen receptor alpha) to CYP1A1 (cytochrome P4501A1 gene) and CYP1B1 promoters in T-47D human breast cancer cells and other cell lines. PCB126 treatment strongly induced CYP1A1 and CYP1B1 mRNA expression that was unaffected by co-treatment with E2 (17beta-oestradiol). PCB104 failed to induce changes in either CYP1A1 or CYP1B1 expression levels. ChIP (chromatin immunoprecipitation) assays show that PCB126, but not PCB104, increased the promoter occupancy by ERalpha to CYP1A1 and CYP1B1 promoters. Co-treatment with PCB126+E2 significantly enhanced the promoter occupancy of ERalpha at CYP1A1, whereas co-treatment with PCB126+4-hydroxytamoxifen or ICI182,780 did not. Competitive binding studies revealed that neither PCB126 nor PCB104 bound to ERalpha. HEK-293 cells (human embryonic kidney-293 cells) stably transfected with ERalpha showed significantly higher PCB126-induced CYP1A1 expression compared with empty vector controls, whereas no increase was observed in cells stably transfected with ERalpha lacking its N-terminal AF1 (activation function-1) domain (ERalphaDeltaAF1). Despite no increase in AHR-mediated gene expression, ChIP assays revealed that ERalphaDeltaAF1 was present at CYP1A1 and CYP1B1 promoters. HC11 mouse mammary cells stably expressing shRNA (small-hairpin RNA) against ERalpha showed an 8-fold reduction in PCB126-dependent Cyp1a1 expression. Our results provide further evidence that AHR agonists induce ERalpha promoter occupancy at AHR target genes through indirect activation of ERalpha, and support a role for ERalpha in AHR transactivation.
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PMID:Co-planar 3,3',4,4',5-pentachlorinated biphenyl and non-co-planar 2,2',4,6,6'-pentachlorinated biphenyl differentially induce recruitment of oestrogen receptor alpha to aryl hydrocarbon receptor target genes. 1751 20

Diindolylmethane (DIM), a biologically active congener of indole-3-carbinol (I3C) derived from cruciferous vegetables, is a promising agent for the prevention of estrogen-sensitive cancers. Both DIM and estrogen affect transcription of genes by binding receptors, such as aryl hydrocarbon receptor (AhR) or estrogen receptors (ER). Gene regulation by DIM and estradiol (E2) can be very complex. While DIM typically binds the AhR, this complex can directly associate with the ER, recruit co-activators that bind to estrogen-responsive promoters, and activate transcription. Alternately, DIM can bind the ER directly. In this study, we have analyzed gene expression using microarray profiling and quantitative real time-polymerase chain reaction in MCF7 breast cancer cells treated with E2 (1 nM) or DIM (25 microM) alone or in combination for 16 h. The interplay of E2 and DIM was reflected in the expression of a subset of genes (<90) in which the combination of E2 and DIM acted either additively or antagonistically to alter gene expression.
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PMID:Interplay of genes regulated by estrogen and diindolylmethane in breast cancer cell lines. 1751 58

Although it is causative for many types of cancers, experimental and epidemiological evidence suggest that 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) may in fact protect against breast cancer. The mechanism(s) for this protection remain unclear. In an attempt to further elucidate this mechanism, we performed a microarray experiment to identify genes that were modulated upon dioxin treatment. We found that dioxin downregulated the messenger RNAs for the G-protein-coupled receptor, CXCR4, as well as its unique chemokine ligand, CXCL12, in MCF-7 breast cancer cells. We demonstrated that the corresponding proteins are also downregulated by dioxin. The interaction between CXCR4 and CXCL12 plays a central role in the metastasis of breast cancer, as disruption of the CXCL12/CXCR4 axis has been shown to limit the metastasis of breast cancer cells to the lung in mice. Utilizing an in vitro chemotaxis assay, we demonstrate that dioxin specifically inhibits the migration of MCF-7 cells toward CXCL12. We also show that dioxin reduces CXCR4 under hypoxia and CXCL12 under estradiol-induced conditions in MCF-7 cells. Finally, as the CXCR4/CXCL12 axis is implicated in the progression of numerous types of cancer, we identified several other cancer cell lines in which dioxin modulates CXCR4 and CXCL12 levels. We therefore propose that one mechanism whereby dioxin may protect against breast cancer is via downregulation of CXCR4 and CXCL12, thereby inhibiting progression of the disease. Further, other nontoxic ligands for the aryl hydrocarbon receptor (selective AHR modulators) may exert their protective effects by a similar mechanism.
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PMID:A proposed mechanism for the protective effect of dioxin against breast cancer. 1751 23

4-Methoxyequilenin (4-MeOEN) is an O-methylated metabolite in equine estrogen metabolism. O-methylation of catechol estrogens is considered as a protective mechanism; however, comparison of the properties of 4-MeOEN with estradiol (E(2)) in human breast cancer cells showed that 4-MeOEN is a proliferative, estrogenic agent that may contribute to carcinogenesis. 4-MeOEN results from O-methylation of 4-hydroxyequilenin, a major catechol metabolite of the equine estrogens present in hormone replacement therapeutics, which causes DNA damage via quinone formation, raising the possibility of synergistic hormonal and chemical carcinogenesis. 4-MeOEN induced cell proliferation with nanomolar potency and induced estrogen response element (ERE)-mediated gene transcription of an ERE-luciferase reporter and the endogenous estrogen-responsive genes pS2 and TGF-alpha. These estrogenic actions were blocked by the antiestrogen ICI 182,780. In the standard radioligand estrogen receptor (ER) binding assay, 4-MeOEN showed very weak binding. To test for alternate ligand-ER-independent mechanisms, the possibility of aryl hydrocarbon receptor (AhR) binding and ER-AhR cross talk was examined using a xenobiotic response element-luciferase reporter and using AhR small interfering RNA silencing in the ERE-luciferase reporter assay. The results negated the possibility of AhR-mediated estrogenic activity. Comparison of gene transcription time course, ER degradation, and rapid activation of MAPK/ERK in MCF-7 cells demonstrated that the actions of 4-MeOEN mirrored those of E(2) with potency for classical and nonclassical estrogenic pathways bracketing that of E(2). Methylation of 4-OHEN may not represent a detoxification pathway because 4-MeOEN is a full, potent estrogen agonist.
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PMID:Activation of estrogen receptor-mediated gene transcription by the equine estrogen metabolite, 4-methoxyequilenin, in human breast cancer cells. 1758 65

The aryl hydrocarbon receptor (AhR) is expressed in estrogen receptor (ER)-positive ZR-75 breast cancer cells. Treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and mRNA levels and also activates inhibitory AhR-ERalpha crosstalk associated with hormone-induced reporter gene expression. In ZR-75 cells grown under hypoxia, induction of these AhR-mediated responses by TCDD was significantly inhibited. This was not accompanied by decreased nuclear AhR levels or decreased interaction of the AhR complex with the CYP1A1 gene promoter as determined in a chromatin immunoprecipitation assay. Hypoxia-induced loss of Ah-responsiveness was not associated with induction of hypoxia-inducible factor-1alpha or other factors that sequester the AhR nuclear translocation (Arnt) protein, and overexpression of Arnt under hypoxia did not restore Ah-responsiveness. The p65 subunit of NFkappaB which inhibits AhR-mediated transactivation was not induced by hypoxia and was primarily cytosolic in ZR-75 cells grown under hypoxic and normoxic conditions. In ZR-75 cells maintained under hypoxic conditions for 24 h, BRCA1 (an enhancer of AhR-mediated transactivation in breast cancer cells) was significantly decreased and this contributed to loss of Ah-responsiveness. In cells grown under hypoxia for 6 h, BRCA1 was not decreased, but induction of CYP1A1 by TCDD was significantly decreased. Cotreatment of ZR-75 cells with TCDD plus the protein synthesis inhibitor cycloheximide for 6 h enhanced CYP1A1 expression in cells grown under hypoxia and normoxia. These results suggest that hypoxia rapidly induces protein(s) that inhibit Ah-responsiveness and these may be similar to constitutively expressed inhibitors of Ah-responsiveness (under normoxia) that are also inhibited by cycloheximide.
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PMID:Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells. 1759 77

The aryl hydrocarbon receptor (AhR) is a receptor/transcription factor which regulates cytochrome P450 (CYP) gene transcription and which is activated by environmental carcinogens, some of which are associated with increased breast cancer risk. Here, we show that the AhR is over-expressed and constitutively active in human and rodent mammary tumors, suggesting its ongoing contribution to tumorigenesis regardless of tumor etiology. AhR regulation of CYP1A1 and CYP1B1 was studied to determine if constitutively active AhR effects the same transcriptional outcomes as environmental chemical-activated AhR. Elevated AhR and CYP1B1 but not CYP1A1 before tumor formation in a rat model of mammary tumorigenesis suggested differential CYP1B1 regulation by a constitutively active AhR. This hypothesis was tested with human mammary gland cell lines which hyper-express AhR and CYP1B1 but which express little or no CYP1A1. CYP1B1 expression was diminished by repression of AhR activity or by AhR knockdown, demonstrating AhR control of basal CYP1B1 levels. ChIP assays demonstrated constitutive AhR binding to both CYP1A1 and CYP1B1 promoters, demonstrating that differential CYP1A1 and CYP1B1 regulation by constitutively active AhR does not result from different amounts of promoter-bound AhR. While increasing AhR binding to both CYP1A1 and CYP1B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin induced CYP1A1 mRNA in both a malignant and non-malignant line but increased only CYP1B1 mRNA in the malignant line, again demonstrating that the level of promoter binding does not necessarily correlate with gene mRNA levels. These studies suggest that constitutively active AhR mediates different molecular outcomes than environmental chemical-activated AhR, and further implicate the AhR in mammary tumorigenesis.
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PMID:Constitutive regulation of CYP1B1 by the aryl hydrocarbon receptor (AhR) in pre-malignant and malignant mammary tissue. 1805 14


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