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1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361004

RESUMO

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.


Assuntos
Acetilcisteína/farmacologia , Carcinogênese/efeitos dos fármacos , Estradiol/farmacologia , Estrona/farmacologia , Quinonas/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Carcinogênese/genética , Adutos de DNA , Estradiol/toxicidade , Estrogênios/farmacologia , Estrogênios/toxicidade , Estrona/toxicidade , Humanos , Quinonas/toxicidade
2.
Public Health Rep ; : 333549211008886, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971104

RESUMO

OBJECTIVES: Chronic exposure to arsenic has been reported as a risk factor for nonmelanoma skin cancer, notably squamous cell carcinoma. However, current knowledge is limited about the association between arsenic exposure and melanoma. Our objectives were to (1) measure the association between total urinary arsenic levels and melanoma compared with nonmelanoma skin cancer and no cancer and (2) analyze the association between water source and melanoma and nonmelanoma skin cancer. METHODS: We collected cross-sectional data from the 2003-2016 cycles of the National Health and Nutrition Examination Survey. We conducted univariate and multivariate logistic regressions. To evaluate the possible association of skin cancer with source of tap water, we calculated odds ratios for participants with melanoma and nonmelanoma skin cancer, compared with participants with no cancer. RESULTS: White race, higher education, higher socioeconomic status, and smoking history were associated with melanoma and nonmelanoma skin cancer in the full study population. After adjusting for age and race/ethnicity, the adjusted odds ratio of participants with >50 µg/L of total urinary arsenic for melanoma or nonmelanoma skin cancer was 1.87 (95% CI, 0.58-6.05) and 2.23 (95% CI, 1.12-4.45) times higher compared with no cancer, respectively. Participants with nonmelanoma skin cancer had 2.06 increased odds of reporting a nonmunicipal water source compared with participants without cancer. CONCLUSIONS: We did not find a relationship between the incidence of melanoma and exposure to arsenic among US adults. Nonmunicipal water sources were associated with nonmelanoma skin cancer and should be further investigated.

3.
Cancer Epidemiol Biomarkers Prev ; 29(10): 2096-2099, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32699078

RESUMO

BACKGROUND: It is biologically plausible that genotoxic estrogens, namely estrogen DNA adducts (EDA), have a role in breast cancer development. Support comes from three prior studies that reported elevated concentrations of EDA relative to estrogen metabolites and conjugates (EDA:EMC) in women with breast cancer relative to control women. METHODS: In postmenopausal women in the Women's Health Initiative (WHI), EDA:EMC in 191 controls was compared with findings in 194 prediagnosis urine samples from breast cancer cases. EDA:EMC determinations were by mass spectrometry as previously described, and logistic regression was employed to estimate ORs. RESULTS: EDA:EMC did not differ in breast cancer cases compared with controls overall [0.93 (95% confidence interval, 0.71-1.23)], with a mean (SD) of 2.3 (0.8) and 2.4 (1.1) in cases and controls, respectively. Similarly, the ratio did not differ when examined by estrogen receptor or recency of biospecimen collection prior to breast cancer. CONCLUSIONS: Despite the demonstrated genotoxic properties of certain catechol estrogens resulting in EDAs, this analysis did not provide evidence for an increased breast cancer risk in relation to an elevated EDA:EMC. IMPACT: This analysis, conducted prospectively within postmenopausal women in the WHI study, suggests that a strong association between EDA:EMC and breast cancer could be ruled out, as this study was powered to detect an OR of 2.2 or greater.

4.
Free Radic Biol Med ; 147: 69-79, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31857234

RESUMO

Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related genetically complex disease characterized by increased oxidative DNA damage and progressive degeneration of corneal endothelial cells (HCEnCs). FECD has a greater incidence and advanced phenotype in women, suggesting a possible role of hormones in the sex-driven differences seen in the disease pathogenesis. In this study, catechol estrogen (4-OHE2), the byproduct of estrogen metabolism, induced genotoxic estrogen-DNA adducts formation, macromolecular DNA damage, and apoptotic cell death in HCEnCs; these findings were potentiated by menadione (MN)-mediated reactive oxygen species (ROS). Expression of NQO1, a key enzyme that neutralizes reactive estrogen metabolites, was downregulated in FECD, indicating HCEnC susceptibility to reactive estrogen metabolism in FECD. NQO1 deficiency in vitro exacerbated the estrogen-DNA adduct formation and loss of cell viability, which was rescued by the supplementation of N-acetylcysteine, a ROS scavenger. Notably, overexpression of NQO1 in HCEnCs treated with MN and 4-OHE2 quenched the ROS formation, thereby reducing the DNA damage and endothelial cell loss. This study signifies a pivotal role for NQO1 in mitigating the macromolecular oxidative DNA damage arising from the interplay between intracellular ROS and impaired endogenous estrogen metabolism in post-mitotic ocular tissue cells. A dysfunctional Nrf2-NQO1 axis in FECD renders HCEnCs susceptible to catechol estrogens and estrogen-DNA adducts formation. This novel study highlights the potential role of NQO1-mediated estrogen metabolite genotoxicity in explaining the higher incidence of FECD in females.


Assuntos
Distrofia Endotelial de Fuchs , Adutos de DNA , Dano ao DNA , Células Endoteliais , Endotélio Corneano , Estrogênios/toxicidade , Feminino , Distrofia Endotelial de Fuchs/genética , Humanos , NAD(P)H Desidrogenase (Quinona)/genética
5.
Proc Natl Acad Sci U S A ; 117(1): 573-583, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31852820

RESUMO

Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.


Assuntos
Citocromo P-450 CYP1B1/metabolismo , Adutos de DNA/efeitos da radiação , Dano ao DNA/efeitos da radiação , Estrogênios/metabolismo , Distrofia Endotelial de Fuchs/etiologia , Raios Ultravioleta/efeitos adversos , Acetilcisteína/administração & dosagem , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Humor Aquoso/efeitos da radiação , Adutos de DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , DNA Mitocondrial/metabolismo , DNA Mitocondrial/efeitos da radiação , Modelos Animais de Doenças , Endotélio Corneano/efeitos dos fármacos , Endotélio Corneano/patologia , Endotélio Corneano/efeitos da radiação , Feminino , Sequestradores de Radicais Livres/administração & dosagem , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/patologia , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença
6.
Horm Cancer ; 10(2-3): 77-88, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30877616

RESUMO

Androgens are thought to cause prostate cancer, but the underlying mechanisms are unclear. Data from animal studies suggest that for androgens to cause prostate cancer, they must be aromatized to estrogen and act in concert with estrogen metabolites. We tested the hypothesis that androgen-receptor and estrogen receptor-mediated effects of androgen and estrogen are necessary, as well as genotoxicity of estrogen metabolites. NBL rats were treated with androgenic and estrogenic compounds for 16-75 weeks through slow-release silastic implants or pellets. Testosterone alone induced cancer in the prostate of 37% of rats. 5α-Dihydrotestosterone, which cannot be converted to estradiol or testosterone, did not cause a significant prostate cancer incidence (4%). Addition of estradiol to 5α-dihydrotestosterone treatment did not markedly enhance prostate cancer incidence (14%), unlike adding estradiol to testosterone treatment which induced a 100% tumor incidence. Testosterone plus estradiol treatment induced a DNA adduct detectable by 32P-postlabeling, oxidative DNA damage (8-hydroxyguanosine), and lipid peroxidation at the site within the prostate where this treatment causes cancers, preceding later cancer formation. The non-estrogenic 4-hydroxy metabolite of estradiol, when combined with testosterone, induced prostatic dysplasia within 16 weeks and, after long-term treatment, a very low incidence of prostate cancer (21%). When an estrogen that cannot be hydroxylated (2-fluoroestradiol) was added to this combined treatment with testosterone and 4-hydroxyestradiol, dysplasia frequency after 16 weeks was doubled. These results strongly support the hypothesis, but additional definitive studies are needed which may identify new targets to interfere with these mechanisms that are clinically feasible in humans.


Assuntos
Androgênios/efeitos adversos , Carcinogênese , Estrogênios/efeitos adversos , Neoplasias da Próstata/induzido quimicamente , Animais , Carcinoma , Adutos de DNA , Dano ao DNA , Di-Hidrotestosterona/metabolismo , Estradiol/metabolismo , Estrogênios de Catecol/química , Guanosina/análogos & derivados , Guanosina/farmacologia , Humanos , Incidência , Masculino , Próstata , Ratos , Receptores de Estrogênio/metabolismo , Testosterona/metabolismo
7.
Chem Res Toxicol ; 32(1): 190-194, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30525503

RESUMO

Studies in Caucasian women have shown that the formation of estrogen-DNA adducts is greater in women at high risk for breast cancer or already diagnosed with the disease. To begin investigating whether the role of estrogens in the etiology of breast cancer is similar in African-American (AA) women, a saliva sample and a spot urine sample were collected from 19 AA women with breast cancer and 23 AA women not diagnosed with breast cancer. In the urine samples, 20 estrogen metabolites, conjugates, and DNA adducts were analyzed by using ultraperformance liquid chromatography/tandem mass spectrometry, and then the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and estrogen conjugates was significantly greater in cases compared to controls (92.4 ± 46.4 vs 38.5 ± 18.9, p < 0.0001). From the saliva samples, genomic DNA was purified and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes, catechol- O-methyltransferase (rs4680) and cytochrome P450 1B1 (rs1056836). There was no association between rs4680 and rs1056836 genotypes and adduct ratios or breast cancer status. This pilot study found higher DNA adduct ratios in women with breast cancer, which suggests that estrogen metabolism is out of balance, and the formation of estrogen-DNA adducts may exert a critical role in breast cancer initiation in AA women.


Assuntos
Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Adulto , Afro-Americanos/genética , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Cromatografia Líquida de Alta Pressão , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , DNA de Neoplasias/urina , Estrogênios/química , Estrogênios/urina , Feminino , Humanos , Pessoa de Meia-Idade , Conformação Molecular , Projetos Piloto , Espectrometria de Massas em Tandem
8.
ACS Omega ; 3(5): 5511-5515, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29876539

RESUMO

Arsenic trioxide (As2O3) is an environmental carcinogen and a putative endocrine disruptor. Resveratrol has been shown to reverse As2O3-induced oxidative damage. In immortalized but nontransformed estrogen receptor α-negative human breast cells (MCF10A), we observed that 25 µM resveratrol ameliorated As2O3-induced cytotoxicity. As2O3, in the presence or absence of 25 µM resveratrol, induced quinone reductase (NAD(P)H quinone dehydrogenase 1), via the induction of NFE2-related factor 2. As2O3 caused a repression of cytochrome P450 (CYP)1B1, but the addition of 25 µM resveratrol rescued the expression of cytochrome P450 1B1 and kept it at a constant level. Therefore, 25 µM resveratrol can modulate the effects of As2O3 on enzymes involved in estrogen metabolism.

9.
Curr Environ Health Rep ; 5(2): 225-232, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29754262

RESUMO

PURPOSE OF REVIEW: Growth-enhancing chemicals used by the beef and dairy industries may be bioavailable to humans via milk, meat, and other environmental matrices. This review evaluates the potential for environmental transport and bioavailability of the active chemical to humans. RECENT FINDINGS: Bovine somatostatin is detectable in milk; however, there is no evidence that the protein persists in the environment nor that it is active in humans. In contrast, steroids are transported through milk and meat to humans where they may exert biological activity. Furthermore, environmental matrices such as raw water and dust may also allow for the environmental transport and bioavailability of steroids to humans. Endogenous and exogenous steroids can be found in the meat, milk, and waste materials produced by cattle. While the concentrations may be low, exposure to these matrices, most notably dairy products made with whole milk, can be a source of exogenous steroids to humans.


Assuntos
Exposição Dietética/análise , Hormônios/análise , Leite/química , Carne Vermelha/análise , Criação de Animais Domésticos , Animais , Bovinos , Indústria de Laticínios , Humanos , Somatostatina/análise , Estados Unidos
10.
Environ Health Insights ; 12: 1178630217751906, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29398918

RESUMO

In 2009, a paper was published suggesting that watersheds provide a geospatial platform for establishing linkages between aquatic contaminants, the health of the environment, and human health. This article is a follow-up to that original article. From an environmental perspective, watersheds segregate landscapes into geospatial units that may be relevant to human health outcomes. From an epidemiologic perspective, the watershed concept places anthropogenic health data into a geospatial framework that has environmental relevance. Research discussed in this article includes information gathered from the literature, as well as recent data collected and analyzed by this research group. It is our contention that the use of watersheds to stratify geospatial information may be both environmentally and epidemiologically valuable.

11.
Int J Cancer ; 141(6): 1078-1090, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28388839

RESUMO

Endogenous estrogens become carcinogens when dangerous metabolites, the catechol estrogen quinones, are formed. In particular, the catechol estrogen-3,4-quinones can react with DNA to produce an excess of specific depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from various types of studies. High levels of depurinating estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, as well as in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Formation of analogous depurinating dopamine-DNA adducts is hypothesized to initiate Parkinson's disease by affecting dopaminergic neurons. Two dietary supplements, N-acetylcysteine and resveratrol complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. When initiation of cancer is blocked, promotion, progression and development of the disease cannot occur. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.


Assuntos
Adutos de DNA/metabolismo , Estrogênios/metabolismo , Neoplasias/etiologia , Neoplasias/prevenção & controle , Doença de Parkinson/etiologia , Doença de Parkinson/prevenção & controle , Animais , Dopamina/metabolismo , Humanos , Neoplasias/metabolismo , Doença de Parkinson/metabolismo , Purinas/metabolismo
12.
J Rare Dis Res Treat ; 2(3): 22-29, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-30854528

RESUMO

Endogenous estrogens become carcinogens when excessive catechol estrogen quinone metabolites are formed. Specifically, the catechol estrogen-3,4-quinones can react with DNA to produce a large amount of specific depurinating estrogen-DNA adducts, formed at the N-3 of Ade and N-7 of Gua. Loss of these adducts leaves apurinic sites in the DNA, which can generate subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of the depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from studies in vitro, in cell culture, in animal models and in human subjects. High levels of estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, and in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Two dietary supplements, N-acetylcysteine and resveratrol, complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these epithelial cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. Blocking initiation of cancer prevents promotion, progression and development of the disease. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.

13.
Clin Transl Med ; 5(1): 12, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26979321

RESUMO

Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma. Depurinating estrogen-DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts could prevent the initiation of human cancer. The dietary supplements N-acetylcysteine and resveratrol inhibit formation of estrogen-DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer. Graphical abstract Major metabolic pathway in cancer initiation by estrogens.

14.
Blood ; 126(15): 1741-52, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26268241

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL) with a poor prognosis. We performed targeted resequencing on 92 cases of PTCL and identified frequent mutations affecting RHOA, TET2, DNMT3A, and isocitrate dehydrogenase 2 (IDH2). Although IDH2 mutations are largely confined to AITL, mutations of the other 3 can be found in other types of PTCL, although at lower frequencies. These findings indicate a key role of epigenetic regulation in the pathogenesis of AITL. However, the epigenetic alterations induced by these mutations and their role in AITL pathogenesis are still largely unknown. We correlated mutational status with gene expression and global DNA methylation changes in AITL. Strikingly, AITL cases with IDH2(R172) mutations demonstrated a distinct gene expression signature characterized by downregulation of genes associated with TH1 differentiation (eg, STAT1 and IFNG) and a striking enrichment of an interleukin 12-induced gene signature. Ectopic expression of IDH2(R172K) in the Jurkat cell line and CD4(+) T cells led to markedly increased levels of 2-hydroxyglutarate, histone-3 lysine methylation, and 5-methylcytosine and a decrease of 5-hydroxymethylcytosine. Correspondingly, clinical samples with IDH2 mutations displayed a prominent increase in H3K27me3 and DNA hypermethylation of gene promoters. Integrative analysis of gene expression and promoter methylation revealed recurrently hypermethylated genes involved in T-cell receptor signaling and T-cell differentiation that likely contribute to lymphomagenesis in AITL.


Assuntos
Epigênese Genética/genética , Linfadenopatia Imunoblástica/classificação , Isocitrato Desidrogenase/genética , Linfoma de Células T/classificação , Mutação/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Células Cultivadas , Estudos de Coortes , Metilação de DNA , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/patologia , Técnicas Imunoenzimáticas , Linfoma de Células T/genética , Linfoma de Células T/patologia , Análise de Sequência com Séries de Oligonucleotídeos
15.
J Altern Complement Med ; 21(6): 321-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25974761

RESUMO

BACKGROUND/OBJECTIVE: A functional medicine approach to reduce breast cancer risk is preferable to early detection and treatment in maintaining breast health. Estrogens are implicated in breast cancer initiation through conversion to metabolites that react with DNA to form specific adducts associated with the development of breast cancer. The purpose of this study was to determine the ability of a defined clinical intervention, the AVERTi-Healthy Breast Program (AHBP), to reduce breast cancer risk conditions likely to develop into breast disease. METHODS: To obtain evidence that risk conditions in breast tissue can be reduced with a defined, multifaceted approach, this small clinical trial of 21 women measured indicators of breast health. A detailed clinical evaluation was conducted with all participants, including identification of physical symptoms, such as areas of tenderness upon palpation. Two laboratory assessments were conducted to determine the efficacy of the AHBP. First, 31 estrogen metabolites, estrogen conjugates, and depurinating estrogen-DNA adducts in urine samples taken before intervention were analyzed. The ratio of DNA adducts to metabolites and conjugates was calculated for each sample. Second, oxidative stress was analyzed by measuring the redox potential of glutathione and cysteine in blood plasma. All assessments were conducted before and after participation. RESULTS: The estrogen adduct ratio and redox potential were improved after 90 days on the AHBP. A significant mean reduction of 3.31 (p=0.03) was observed in the adduct ratio, along with a significant improvement in the redox potential of 3.80 (p=0.05). The significant change in the adduct ratio occurred in women whose oxidative stress profile also improved. CONCLUSION: These significant within-individual decreases suggest that the AHBP can reduce the risk for breast cancer in a relatively short time.


Assuntos
Neoplasias da Mama/prevenção & controle , Mama/fisiologia , Promoção da Saúde , Serviços de Saúde da Mulher , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Humanos , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Projetos Piloto
16.
Open J Prev Med ; 4(6): 429-437, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25431744

RESUMO

BACKGROUND: Estrogen exposure plays a role in breast cancer (BC) development. A novel estrogen biomarker, the estrogen DNA adduct (EDA) ratio, was shown to be elevated in women at high-risk of BC and among BC cases. Modifiable factors may impact the EDA ratio, with studies demonstrating that resveratrol reduces EDA ratio in vitro. We sought to examine the hypothesis that dietary intake of fruits and vegetables is inversely associated with EDA ratio. METHODS: This analysis was conducted in 53 pre-menopausal, healthy women aged 40-45 years from a cross-sectional study in which participants provided first-void urine samples and 3-day food records. Urine samples were analyzed using ultraperformance liquid chromatography/tandem mass spectrometry. The EDA ratio was calculated as the estrogen-DNA adducts divided by estrogen metabolites and conjugates. A trend test was used to assess associations between tertiles of dietary intake using linear regression. RESULTS: After adjustment for age, total energy, percent adiposity, serum estradiol and estrone-sulfate, we observed inverse associations of EDA ratio with carbohydrate consumption (P=0.01) and vegetable intake (P =0.01). EDA ratio was inversely associated with 5 botanical groups (Chenopodiaceae: P=0.02; Umbelliferae: P=0.03; Compositae: P=0.01; Ericaceae: P=0.01; Musaceae: P=0.03) but not fruit intake overall. CONCLUSION: Although these data require replication before conclusions are drawn, this report suggests an inverse association between vegetable and carbohydrate consumption and EDA ratio. IMPACT: While more information is still needed, these findings suggest a link between dietary intake and a biomarker that is both associated with high-risk BC status and associated with modifiable factors.

17.
Steroids ; 92: 96-100, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25278253

RESUMO

Breast cancer is the second leading cause of cancer deaths in women in the United States. Diethylstilbestrol (DES) is a synthetic estrogen that has been shown to cause cancer in animals and humans, altering cell viability as well as inducing DNA damage. Diallyl sulfide (DAS) is a garlic organosulfide that has been shown to inhibit both the initiation and promotion phases of cancer in vivo and in vitro, as well as reduce the risk of cancer in epidemiological studies. MCF-10A cells, regarded as a normal breast epithelial cell line, were treated with varying concentrations of DES, DAS or various dose combinations of DES and DAS concomitantly, and assessed for cell viability, DNA strand breaks, and lipid peroxidation. DES (10µM) in combination with 1, 10, or 100µM DAS resulted in a 31%, 34%, or 36% respective increase in cell viability compared to the DES treatment alone, after 24h. At the same time point, 1, 10, and 100µM DAS were all effective in significantly reducing DES (100µM)-induced strand breaks to near that of the vehicle control. Additionally, 1µM DAS was effective in significantly reducing DES (100µM)-induced lipid peroxidation after 3h. The results of this research suggest that DAS is effective in recovering cell viability, attenuating DNA strand breaks, and decreasing lipid peroxidation in MCF-10A cells.


Assuntos
Compostos Alílicos/farmacologia , Dietilestilbestrol/farmacologia , Sulfetos/farmacologia , Compostos Alílicos/química , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dietilestilbestrol/química , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Sulfetos/química
18.
Mol Aspects Med ; 36: 1-55, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23994691

RESUMO

Elucidation of estrogen carcinogenesis required a few fundamental discoveries made by studying the mechanism of carcinogenesis of polycyclic aromatic hydrocarbons (PAH). The two major mechanisms of metabolic activation of PAH involve formation of radical cations and diol epoxides as ultimate carcinogenic metabolites. These intermediates react with DNA to yield two types of adducts: stable adducts that remain in DNA unless removed by repair and depurinating adducts that are lost from DNA by cleavage of the glycosyl bond between the purine base and deoxyribose. The potent carcinogenic PAH benzo[a]pyrene, dibenzo[a,l]pyrene, 7,12-dimethylbenz[a]anthracene and 3-methylcholanthrene predominantly form depurinating DNA adducts, leaving apurinic sites in the DNA that generate cancer-initiating mutations. This was discovered by correlation between the depurinating adducts formed in mouse skin by treatment with benzo[a]pyrene, dibenzo[a,l]pyrene or 7,12-dimethylbenz[a]anthracene and the site of mutations in the Harvey-ras oncogene in mouse skin papillomas initiated by one of these PAH. By applying some of these fundamental discoveries in PAH studies to estrogen carcinogenesis, the natural estrogens estrone (E1) and estradiol (E2) were found to be mutagenic and carcinogenic through formation of the depurinating estrogen-DNA adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. These adducts are generated by reaction of catechol estrogen quinones with DNA, analogously to the DNA adducts obtained from the catechol quinones of benzene, naphthalene, and the synthetic estrogens diethylstilbestrol and hexestrol. This is a weak mechanism of cancer initiation. Normally, estrogen metabolism is balanced and few estrogen-DNA adducts are formed. When estrogen metabolism becomes unbalanced, more catechol estrogen quinones are generated, resulting in higher levels of estrogen-DNA adducts, which can be used as biomarkers of unbalanced estrogen metabolism and, thus, cancer risk. The ratio of estrogen-DNA adducts to estrogen metabolites and conjugates has repeatedly been found to be significantly higher in women at high risk for breast cancer, compared to women at normal risk. These results indicate that formation of estrogen-DNA adducts is a critical factor in the etiology of breast cancer. Significantly higher adduct ratios have been observed in women with breast, thyroid or ovarian cancer. In the women with ovarian cancer, single nucleotide polymorphisms in the genes for two enzymes involved in estrogen metabolism indicate risk for ovarian cancer. When polymorphisms produce high activity cytochrome P450 1B1, an activating enzyme, and low activity catechol-O-methyltransferase, a protective enzyme, in the same woman, she is almost six times more likely to have ovarian cancer. These results indicate that formation of estrogen-DNA adducts is a critical factor in the etiology of ovarian cancer. Significantly higher ratios of estrogen-DNA adducts to estrogen metabolites and conjugates have also been observed in men with prostate cancer or non-Hodgkin lymphoma, compared to healthy men without cancer. These results also support a critical role of estrogen-DNA adducts in the initiation of cancer. Starting from the perspective that unbalanced estrogen metabolism can lead to increased formation of catechol estrogen quinones, their reaction with DNA to form adducts, and generation of cancer-initiating mutations, inhibition of estrogen-DNA adduct formation would be an effective approach to preventing a variety of human cancers. The dietary supplements resveratrol and N-acetylcysteine can act as preventing cancer agents by keeping estrogen metabolism balanced. These two compounds can reduce the formation of catechol estrogen quinones and/or their reaction with DNA. Therefore, resveratrol and N-acetylcysteine provide a widely applicable, inexpensive approach to preventing many of the prevalent types of human cancer.


Assuntos
Carcinógenos/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Adutos de DNA/toxicidade , Estradiol/metabolismo , Estrogênios de Catecol/metabolismo , Estrona/metabolismo , Mutagênicos/toxicidade , Neoplasias/induzido quimicamente , Animais , Biomarcadores Tumorais/metabolismo , Carcinógenos/metabolismo , Adutos de DNA/metabolismo , Feminino , Humanos , Masculino , Mutagênicos/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade
19.
Int J Cancer ; 134(10): 2414-23, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24170413

RESUMO

Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer.


Assuntos
Adutos de DNA/urina , DNA de Neoplasias/urina , Estrogênios/urina , Idoso , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP1B1 , Adutos de DNA/química , Adutos de DNA/metabolismo , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Estrogênios/química , Estrogênios/metabolismo , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/urina , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Saliva/química , Saliva/metabolismo , Espectrometria de Massas em Tandem
20.
Carcinogenesis ; 34(11): 2587-92, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23843041

RESUMO

Sulforaphane (SFN) is a potent inducer of detoxication enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase (GST) via the Kelch-like erythroid-derived protein with CNC homology-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signaling pathway. NQO1 reduces the carcinogenic estrogen metabolite, catechol estrogen-3,4-quinone, whereas GSTs detoxify it through conjugation with glutathione. These 3,4-quinones can react with DNA to form depurinating DNA adducts. Thus, SFN may alter estrogen metabolism and thus protect against estrogen-mediated DNA damage and carcinogenesis. Human breast epithelial MCF-10A cells were treated with either vehicle or SFN and either estradiol (E2) or its metabolite 4-hydroxyestradiol (4-OHE2). 4-Hydroxy-derived estrogen metabolites and depurinating DNA adducts formed from E2 and its interconvertable metabolite estrone (E1) were analyzed by mass spectrometry. Levels of the depurinated adducts, 4-OHE1/2-1-N3Adenine and 4-OHE1/2-1-N7Guanine, were reduced by 60% in SFN-treated cells, whereas levels of 4-OCH3E1/2 and 4-OHE1/2-glutathione conjugates increased. To constitutively enhance the expression of Nrf2-regulated genes, cells were treated with either scrambled or siKEAP1 RNA. Following E2 or 4-OHE2 treatments, levels of the adenine and guanine adducts dropped 60-70% in siKEAP1-treated cells, whereas 4-OHE1/2-glutathione conjugates increased. However, 4-OCH3E1/2 decreased 50% after siKEAP1 treatment. Thus, treatment with SFN or siKEAP1 has similar effects on reduction of depurinating estrogen-DNA adduct levels following estrogen challenge. However, these pharmacologic and genetic approaches have different effects on estrogen metabolism to O-methyl and glutathione conjugates. Activation of the Nrf2 pathway, especially elevated NQO1, may account for some but not all of the protective effects of SFN against estrogen-mediated DNA damage.


Assuntos
Anticarcinógenos/farmacologia , Mama/efeitos dos fármacos , Adutos de DNA/efeitos dos fármacos , Estrogênios/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Apoptose , Western Blotting , Mama/citologia , Mama/metabolismo , Proliferação de Células , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Técnicas Imunoenzimáticas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Espectrometria de Massas em Tandem
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