UMLS:C0006142 - FACTA Search

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

Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants that have been extensively studied for multiple toxicological endpoints in both laboratory animals and humans. The purpose of this study was to investigate the estrogenicity of PAHs in the human breast cancer cell line MCF-7. We investigated 14 PAHs for their ability to bind either the estrogen receptor (ER) or the aryl hydrocarbon receptor (AhR) and to activate target gene expression. PAHs were tested in a human recombinant estrogen receptor (hrER) competitive binding assay, and in both an estrogen response element (ERE)- and xenobiotic response element (XRE)-mediated reporter gene assay. We used quantitative RT-PCR to examine selected PAHs that showed activity in the ERE reporter gene assay for their ability to upregulate estrogen-responsive genes HEM45, progesterone receptor, and pS2, and the aryl hydrocarbon-responsive CYP1A1 gene. None of the 14 PAHs bound the hrER, but five of the PAHs (anthracene, B[a]A, chrysene, B[b]F, and B[a]P) induced ER-reporter activity. This activity was dependent on the metabolism of PAHs in MCF-7 cells via the AhR pathway, which resulted in the formation of metabolites that bound the ER. None of the five PAHs that induced the ER-reporter were found to upregulate estrogen-responsive genes, yet four of the five PAHs induced AhR-dependent CYP1A1 gene expression. In contrast, a metabolite of B[a]P, 3'OH-B[a]P, and a PCB metabolite, 4'OH-2,4,6-BP, did weakly upregulate all three estrogen-responsive genes. Data from these studies indicate that induction of ER-reporter activity alone does not necessarily parallel endogenous gene transcription, and that the reporter gene assay may detect interactions that are not functional in vivo.
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PMID:Differential action of polycyclic aromatic hydrocarbons on endogenous estrogen-responsive genes and on a transfected estrogen-responsive reporter in MCF-7 cells. 1505 Apr 8

The standard paradigm providing a general mechanistic explanation for the association of cumulative, excessive oestrogen exposure and breast cancer risk is that the proliferative stimulus provided by 17 beta-estradiol (E2) leads to the appearance of spontaneous mutations. Thus, the key contribution of E2 is the stimulation of breast epithelial cell proliferation. However, mounting evidence supports a complimentary pathway involving direct (oestrogen-quinone DNA adducts) and indirect (oxidative DNA damage via redox cycling) genotoxicity originating from oestrogen metabolites. While mutations in high penetrance genes such as BRCA1, BRCA2 and p53 confer a high risk for an individual, they represent a low overall attributable risk due to low allele frequencies in the population. On the other hand, mutations in phases I and II enzyme genes involved in xenobiotic and endobiotic metabolism, including genes encoding CYP1A1, N-acetyltransferase 2 and glutathione-S-transferase (GST) isoforms M1 (null), T1 (null), and P1 (low-activity allele), might confer a low relative cancer risk for an individual. However, because these mutations seem to be common among individuals, they represent a high attributable risk category of genes. The intent of this review is to examine current literature on the molecular epidemiology of breast cancer with emphasis on the role of polymorphisms in high and low penetrance genes on susceptibility to breast cancer.
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PMID:Molecular epidemiology of breast cancer: a review. 1505 43

Lung cancer is the leading cause of cancer death in US women and is responsible for as many deaths as breast cancer and all gynecological cancers combined. Most lung cancer is caused by cigarette smoke. Despite all that is known about the devastating effects of cigarettes, one quarter of women in the United States continue to smoke. Women are targeted in tobacco advertising, and teenage girls are often drawn to cigarette smoking under a variety of social pressures. Following the increase in smoking, the death rate from lung cancer in US women rose 600% from 1930 to 1997. Women may be more susceptible than men to the carcinogenic properties of cigarette smoke. In addition, differences in the biology of lung cancer exist between the 2 sexes with higher levels of DNA adduct formation, increased CYP1A1 expression, decreased DNA repair capacity, and increased incidence of K-ras gene mutations in women. The novel estrogen receptor beta has also been detected in lung tumors and suggests that estrogen signaling may have a biological role in tumorigenesis. Given these differences and given the enormous toll this disease has on US women, undertaking sex-specific research in lung cancer is crucial. Finally, disseminating information about this epidemic may prevent a similar epidemic in other parts of the world where women are just now becoming addicted to tobacco.
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PMID:Lung cancer in US women: a contemporary epidemic. 1508 4

A short-term effect of a meal of fried meat is a postprandial induction of hepatic and intestinal cytochrome P450 activity. In order to identify the components responsible for this effect we investigated the potency of food derived genotoxic heterocyclic aromatic amines (HA) to induce CYP1A1 in vitro. In two cell lines, the rat hepatoma cell line H4IIE and the human breast cancer cell line MCF-7, we investigated 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeAC), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and Harman representing the different classes of HA at concentrations from 10(-8) to 10(-4) M. Induction of CYP1A1 was analysed on the mRNA level by semi-quantitative RT-PCR and the protein level (western blot using specific antibodies). The relative order of enzyme induction was Trp-P-1 with 1.4 x 10(-6) M (EC50 compared to TCDD 10(-9) M), MeAalphaC (1.4 x 10(-5)), Harman (2.1 x 10(-4)) and MeIQx (1.0 x 10(-3)). Furthermore, CYP1A1 enzyme activity was analysed as ethoxyresorufin-O-deethylase. While protein and mRNA analyses gave similar results, competitive inhibition impaired the enzyme activity assay. Inhibition of CYP1A1 activity was determined using microsomes of heterologous expressed CYP1A1. This dose-dependent inhibitory activity paralleled the induction potency. These results compare well with earlier data published for hepatic enzyme induction by HA observed in animal experiments. However, since the observed activities are rather weak and the amounts of HA ingested with a meal are low, there may be other factors involved in the observed postprandial enzyme induction in humans. On the other hand, concentrations in the micromolar range that are reached in high dosage animal experiments with HA may well influence cytochrome activity and, thus, influence the experimental outcome of these studies.
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PMID:Modulation of cytochrome P450 1A1 by food-derived heterocyclic aromatic amines. 1514 96

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous pollutant and promoter of carcinogenesis with both estrogenic and antiestrogenic effects in mammal epithelium. Zearalenone (ZEA) is a naturally occurring estrogenic contaminant of moldy feeds and is present in high concentrations in dairy products and cereals. Numerous studies describe a possible correlation between xenoestrogens and breast cancer risk. A potential mechanism for the etiology of breast cancer involves altered cytochrome P450 (CYP) enzymes. Since cocontamination of multiple compounds in our environmental and occupational circumstances likely happens and since few studies have addressed the molecular consequences of combinations of contaminants, we decided to investigate the effects of ZEA on basal and TCDD-induced mRNA expression and enzymic activity of CYP1A1 and CYP1B1 in human breast cancer MCF-7 cells. CYP1A1 enzyme activity was measured by the CYP1A1-referential activity assay, ethoxyresorufin O-deethylase (EROD), in MCF-7 cells. To investigate CYP1B1 activity, we employed the microsomal EROD assay prepared from baculovirus-infected insect cells expressing human cDNA CYP1B1. Reverse transcription-polymerase chain reaction was used to detect mRNA expression of CYP1A1 and CYP1B1 in MCF-7 cells. The results demonstrated that 10nM TCDD could readily induce a significant increase in the enzyme activity and mRNA expression of CYP1A1 in MCF-7 cells and 5 nM estradiol (E2) significantly reduced both basal and TCDD-induced activity and mRNA expression in MCF-7 cells. The same pattern was observed with 50nM ZEA. The estrogen receptor antagonist 4-hydroxytamoxifen could attenuate these inhibitive effects of both E2 and ZEA. Interestingly, Both E2 and ZEA could promote basal and TCDD-induced CYP1B1 activity but with no effect on CYP1B1 mRNA expression. These results suggest that the effect of ZEA on the TCDD-induced CYP1A1 activity and gene expression involved the estrogen receptor pathway and that the increase in the CYP1B1/CYP1A1 ratio underlying the basal or TCDD-treated condition might constitute one of the mechanisms underlying the synergic carcinogenic action of these compounds.
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PMID:Effects of zearalenone on mRNA expression and activity of cytochrome P450 1A1 and 1B1 in MCF-7 cells. 1515 72

This study investigated the ability of amitraz, a formamidine insecticide, to induce cytochrome P450-dependent monooxygenases and to disrupt estrogenic activity in human breast cancer MCF-7 cells and immature female rats. In MCF-7 cells, treatment with 10 microM amitraz for 24 h increased 7-ethoxyresorufin O-deethylase activity in cell homogenate. Treatment of MCF-7 cells with 1 and 10 microM amitraz for 3 h replaced previously bound [(3)H]17beta-estradiol (E(2)) from estrogen receptors. Treatment with 0.1 and 1 microM amitraz for 2 days inhibited [(3)H]thymidine incorporation into the DNA of MCF-7 cells while the inhibition was blocked in cells co-treated with 1 nM E(2) and amitraz. In immature female rats, treatment with 50 mg/kg amitraz intraperitoneally for 3 days increased cytochrome P450 content, 7-ethoxyresorufin, methoxyresorufin and pentoxyresorufin O-dealkylases, and benzo[a]pyrene hydroxylase activities in liver microsomes. The results of immunoblot analysis revealed that amitraz induced liver microsomal CYP1A1/2, 2B1/2B2, and 3A proteins. Treatment with 10 and 25 mg/kg amitraz for 3 days dose-dependently decreased uterine weight and peroxidase activity in immature female rats while the decreases were blocked in rats co-treated with 10 microg/kg E(2) and 10 or 25 mg/kg amitraz. These in vitro and in vivo findings suggest that amitraz induces multiple forms of P450 and exerts weak antiestrogenic activity.
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PMID:Effects of amitraz on cytochrome P450-dependent monooxygenases and estrogenic activity in MCF-7 human breast cancer cells and immature female rats. 1535 Jun 76

Estrogens and their oxidative metabolites, the catechol estrogens, have been implicated in the development of breast cancer; yet, relatively little is known about estrogen metabolism in the breast. To determine how the parent hormone, 17 beta-estradiol (E(2)), is metabolized, we used recombinant, purified phase I enzymes, cytochrome P450 (CYP) 1A1 and 1B1, with the phase II enzymes catechol-O-methyltransferase (COMT) and glutathione S-transferase P1 (GSTP1), all of which are expressed in breast tissue. We employed both gas and liquid chromatography with mass spectrometry to measure E(2), the catechol estrogens 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)), as well as methoxyestrogens and estrogen-GSH conjugates. The oxidation of E(2) to 2-OHE(2) and 4-OHE(2) was exclusively regulated by CYP1A1 and 1B1, regardless of the presence or concentration of COMT and GSTP1. COMT generated two products, 2-methoxyestradiol and 2-hydroxy-3-methoxyestradiol, from 2-OHE(2) but only one product, 4-methoxyestradiol, from 4-OHE(2). Similarly, GSTP1 yielded two conjugates, 2-OHE(2)-1-SG and 2-OHE(2)-4-SG, from the corresponding quinone 2-hydroxyestradiol-quinone and one conjugate, 4-OHE(2)-2-SG, from 4-hydroxyestradiol-quinone. Using the experimental data, we developed a multicompartment kinetic model for the oxidative metabolism of the parent hormone E(2), which revealed significant differences in rate constants for its C-2 and C-4 metabolites. The results demonstrated a tightly regulated interaction of phase I and phase II enzymes, in which the latter decreased the concentration of catechol estrogens and estrogen quinones, thereby reducing the potential of these oxidative estrogen metabolites to induce DNA damage.
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PMID:In vitro model of mammary estrogen metabolism: structural and kinetic differences between catechol estrogens 2- and 4-hydroxyestradiol. 1537 60

This cross-sectional study examined if polymorphisms in genes that code for enzymes involved in the production and metabolism of estrogens are associated with mammographic density, a strong predictor of breast cancer risk. The study included 328 healthy women of different ethnicities who underwent mammographic screening and donated a blood or mouthwash sample for DNA analysis. After digitizing cranio-caudal views of the mammograms, we performed computer-assisted mammographic density assessment. Following DNA extraction, samples were analyzed for polymorphisms in the COMT (Val158Met), CYP1A1 (Ile462Val), CYP1B1 (Val432Leu), CYP1A2 (*1F) and CYP17 (T27C) genes using PCR-RFLP. Breast density was lower in Caucasians than in Asians. Caucasian women were less likely to carry the CYP1A1 variant allele and more likely to carry the variant alleles for CYP1B1 and COMT than women with Asian or Hawaiian ancestry. The low-activity COMT and CYP1A2 variant alleles were weakly related to lower percent mammographic density after adjustment for age, ethnicity, body mass index and reproductive variables (p for gene-dosage =0.08 and 0.05, respectively). These relations were observed in premenopausal women only and were similar in direction and magnitude after stratification by ethnicity. We found no significant associations between breast density and the variant alleles for CYP1A1, CYP1B1 and CYP17. Our data suggest lower mammographic density for women carrying the COMT and CYP1A2 variant alleles than for women carrying the common alleles, though this is the opposite of what is commonly hypothesized from the enzyme function.
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PMID:An investigation of mammographic density and gene variants in healthy women. 1538 51

Metabolic activation and inactivation of potential genotoxic agents occur by Phase I and Phase II enzymes in multiple interactions. An expanding body of literature demonstrates that ethnic differences in breast cancer incidence may be partly caused by host genetic factors particularly genetic polymorphisms of these carcinogen-metabolizing enzymes. The present case-control study aimed at identification of such low penetrance breast cancer susceptibility genes in 224 Indian women and to investigate the potential effects of their polymorphisms on sporadic breast cancer risk. The main objective of the study was to evaluate the effects of genetic polymorphisms of the xenobiotic metabolizing genes CYP1A1, GSTM1 and GSTT1 on breast cancer risk by PCR-RFLP and DNA sequencing. Our results showed a significant association between CYP1A1 m1, m2 polymorphisms and breast cancer risk; however there was a lack of association between GSTM1 null deletion and breast cancer. The associations of CYP1A1, GSTM1 and GSTT1 genotypes with breast cancer risk were more pronounced among the pre-menopausal patients. Combined genotype analysis revealed the CYP1A1 m2 ValVal-GSTM1 homozygous null deletion genotype combinations to be associated with the highest risk of breast cancer (OR=10.3, 95% CI=1.2-86.1). Correlations with clinicopathological factors and treatment outcome were also analyzed for predicting disease free survival by univariate and multivariate analysis. Significant differences in disease free survival between the wild and polymorphic genotypes were observed only for CYP1A1 m2, GSTT1 genotypes. Our results based on the analysis of functionally relevant polymorphisms in these low penetrance genes may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer. Such genotype analysis resulting in a high-risk profile holds considerable promise for individualizing screening and therapeutic intervention in breast cancer. Hence, the present study may provide strong supportive evidence for genetic interactions in the etiology of breast cancer.
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PMID:Role of xenobiotic metabolizing gene polymorphisms in breast cancer susceptibility and treatment outcome. 1572 14

Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women (after lung cancer). The etiology of breast cancer is still poorly understood with known breast cancer risk factors explaining only a small proportion of cases. Risk factors that modulate the development of breast cancer discussed in this review include: age, geographic location (country of origin) and socioeconomic status, reproductive events, exogenous hormones, lifestyle risk factors (alcohol, diet, obesity and physical activity), familial history of breast cancer, mammographic density, history of benign breast disease, ionizing radiation, bone density, height, IGF- 1 and prolactin levels, chemopreventive agents. Additionally, we summarized breast cancer risk associated with the following genetic factors: breast cancer susceptibility high-penetrance genes (BRCA1, BRCA2, p53, PTEN, ATM, NBS1 or LKB1) and low-penetrance genes such as cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S-transferase family (GSTM1, GSTP1), alcohol and one-carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFalpha or HSP70). All these factors contribute to a better understanding of breast cancer risk. Nonetheless, in order to evaluate more accurately the overall risk of breast tumorigenesis, novel genetic and phenotypic traits need to be identified.
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PMID:Understanding breast cancer risk -- where do we stand in 2005? 1578 78

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